MX2008001718A

MX2008001718A - Novel cysteine protease inhibitors and their therapeutic applications

Info

Publication number: MX2008001718A
Application number: MX/A/2008/001718A
Authority: MX
Inventors: Guedat Philippe; Boissy Guillaume; Borgcapra Catherine; Colland Frederic; Daviet Laurent; Formstecher Etienne; Jacq Xavier; Rain Jeanchristophe; Delansorne Remi; Vallese Stefania; Colombo Matteo
Original assignee: Boissy Guillaume; Borgcapra Catherine; Colland Frederic; Colombo Matteo; Daviet Laurent; Delansorne Remi; Formstecher Etienne; Guedat Philippe; Hybrigenics Sa; Jacq Xavier; Rain Jeanchristophe; Vallese Stefania
Priority date: 2005-08-05
Filing date: 2008-02-05
Publication date: 2008-09-02

Abstract

The present invention concerns new compounds of formula (I), their process of preparation and their therapeutic use.

Description

PROTEASA PROTEASA INHIBITORS AND THEIR THERAPEUTIC APPLICATIONS DESCRIPTION OF THE INVENTION The present invention relates to new inhibitors of cysteine protease, its preparation process and its therapeutic use. The protease can be categorized based on its substrate specificities or catalysis mechanisms. On the basis of the mechanism of peptide hydrolysis, five important classes of protease are known: serine, cysteine, aspartic, threonine and metallo proteases. The cysteine protease comprises, inter alia, deubiquitination enzymes, caspases, cathepsins, calpains as well as parasite, viral, or bacterial cysteines proteases. Deubiquitination enzymes include ubiquitin-specific proteases (USPs) and carboxy ubiquitin hydrolases (UCHs). Broadly speaking, ubiquitin in the path regulates the degradation of the protein and is more particularly involved in cancer, in neurodegenerative diseases such as Alzheimer's Disease, Parkinson's Disease, in inflammation, in viral infectivity and latency (in particular for virus 1 of the herpes simplex, Epstein-Barr virus, Coronavirus SARS), or in cardiovascular diseases (Chem. Rev. 1997, 97, pp. 133-171; Chem. Rev. REF .: 190074 2002, 102, pp. 4459-4488; Biochem 2003, 134, pp. 9-18, J.

Virology, 2005, 79 (7), p. 4550-4551; Cardiovasc. Res. 2004, 61, p. 11-21). The layers have been shown to be involved in apoptosis and thus are targets in hepatitis, liver failure, inflammation, ischemic heart failure, renal failure, neurodegeneration, deafness, diabetes, or stroke (J.

Pharmacol Exp. Ther., 2004, 308 (3), p. 1191-1196, J. Cell. Physiol., 2004, 200 (2), p. 177-200; Kidney Int, 2004, 66 (2), p. 500-506; Am. J. Pathol. , 2004, 165 (2), p. 353-355; Mini Rev. Chem., 2004, 4 (2), p. 153-165; Otol. Neurotol., 2004, 25 (4), p. 627-632; Ref. 7, 21, 22, 23, 24, 25. Cathepsins have generally been shown to be involved in cancer and metastasis, inflammation, immunology / immunoregulation (Eur. Respir J., 2004, 23 (4), p. 620-628) and atherosclerosis (Ageing Res. Rev. 2003, 2 (4), p. 407-418). More particularly, cathepsins include cathepsin B and type B which is involved in cancer and metastasis, and arthritis (Cancer Metastasis Rev., 2003, 22 (2-3), p 271-286; Biol. Chem., 2003 , 384 (6), pp. 845-854 and Biochem.

Soc. Symp., 2003, 70, p. 263-276), cathepsin D, is involved in particular in cancer and metastasis (Clin. Exp. Metastasis, 2004, 21 (2), p.91-106), cathepsin K acts in osteoporosis and arthritis (Int. Pharm., 2004, 277 (1-2), pp. 73-79), cathepsin S which shows that it plays a role in the presentation of the antigen in immunology (Drug News Perspective, 2004, 17 (6), p. 357-363). Calpains play a role in aging in general (Ageing Res. Rev. 2003, 2 (4), p.407-418), as well as diabetes (Mol.Cell. Biochem., 2004, 261 (1), p. 161-167) and cataracts (Trends Mol. Med., 2004, 10 (2), pp. 78-84) more particularly. Viral cysteine proteases are identified in rhinovirus, poliovirus, hepatitis A virus, hepatitis C virus, adenovirus, or coronavirus SARS (Chem. Rev. 1997, 97, pp. 133-171; Chem. Rev. 2002, 102 , p.4459-4488; J. Virology, 2005, 79 (7), pp. 4550-4551 and Acta Microbiol, Immunol., Hung., 2003, 50 (1), p.95-101). Bacterial cysteines proteases include estrepatopain, staphylococcal cysteine protease, clostripain, or gingipains; yeasts such as Aspergillus flavue have also been shown to express cysteine proteases which can be a virulence factor (Chem. Rev. 1997, 97, pp. 133-171). The parasitic cysteine proteases are reviewed in Molecular & Biochemical Parasitology (2002, 120, pp. 1-21) and Chem. Rev. (2002, 102, pp. 4459-448S) for example. It should be noted that the parasitic agents responsible for most parasitic diseases make use of their own cysteine proteases at some point or another of their infective, nutritive or reproductive cycles.; such diseases include malaria, Chagas disease, African trypanosomiasis, leishmaniasis, giardiasis, trichomoniasis, amoebiasis, crypto-sporidia, toxoplamyiasis, schistosomiasis, fasciolasis, onchocerciasis, and other infections by some other flat or round worms. Therefore, novel classes of cysteine protease inhibitors of significant importance in a wide range of diseases and pathological conditions are identified. The cyano-pyrazine derivatives have been described, mainly as transport agents for electrophotographic photoreceptors (O03 / 055853, JP200128885, JP200122316, JP07281460, JP07179440, JP07098508, JP06345742, JP07175235, JP07199487, JP07199486, JP07281460 and Helvética Chemica Acta, 1986, 69 ( 4), 793-802, Tetrahedron Letters 1974, 45, 3967-70, J. Heteterocyclic Chemistry, 1972, 9 (6), 1399-401, Tetrahedron Letters, 1990, 31 (49), 7215-18). However, it has never been described or suggested that cyano-pyrazine derivatives can inhibit cysteine proteases. According to a first objective, the present invention relates to a compound of the formula (I) (I) where: m is 0; 1 or 2, wherein when m = 0, - (X (R2) m ') m is none, such that it forms an open ring or a single bond; n is 0, 1 or 2, wherein when n = 0, - (Y (R7) n-) n - is none, such that it forms an open ring or a single bond; m 'and n' are independently 0, 1 or 2; X is a carbon atom or S or N; And it is a carbon atom, or S or N; With the proviso that m and n are not simultaneously 0; it is either a double or single link, as appropriate; it is either none or a simple link, as appropriate; Rl is chosen from the group consisting of H, CN, Hal, OAlq, OH, NRCN, C (CN) = C (OH) (OAlq), SR, NRRY (Alq) p-C (O) NRR ', Heterocycle, Aryl, Heteroaryl, where Alk, Aryl, Heteroaryl, heterocycle are optionally substituted by Hal, NRRY CN, OH, CF3, Aryl, Heteroaryl, OAlq, Where p is 0 or 1; R3, R4, R5, R6 are each identical or different and are independently selected from the group consisting of H, OAlq, Alk, Hal, NRRY CN, OH, CF3, Aryl, Heteroaryl; R2 is selected from the group consisting of H, 0, OH, N-OH, N-Aryl, N-OAlq, N-0-Aryl, NO-Alk-Aryl, N-NR-CONRRY N-0-CO-Alk , or 2 R2 is linked to the same X is formed together with X mentioned above; wherein Alk, Aryl or heterocycle are optionally substituted by OAlq, Alk, Hal, NRRYCN, OH, CF3, OAril, -CO- (NR-Alq-CO) p-OAlq, -CO (NR-Alq-CO) p -OH, where p 'is 0 or 1; R7 is selected from the group consisting of H, 0, OH, N-OH, N-Aryl, N-OAlq, N-0-Aryl, NO-Alk-Aryl, N-NR-CONRRY N-0-C0-Alk , or 2 R7 is linked to the same Y is formed together with Y heterocycle mentioned above; wherein Alk, Aryl or heterocycle are optionally substituted by OAlq, Alk, Hal, NRRYCN, OH, CF3, OAril, -CO- (NR-Alq-C0) p-0Alq, -C0 (NR-Alq-C0) p-0H, where p 'is 0 or 1; R and R 'are each identical or different and are independently chosen from the group consisting of H, Alk, wherein Alk is optionally substituted by Hal, NRRY CN, OH, CF3, Aryl, Heteroaryl; or its pharmaceutically acceptable salts, hydrates, or hydrated salts, or the polymorphic crystalline structures of these compounds or their optical isomers, racemates, diastereomers or enantiomers, with the exception of compounds where: R3, R4, R5, R6 = H, RI = CN, - (X (R2) m-) m- represents a single bond, and - (Y (R7) n) n- represents -C (= N-OH) - or -C (= N- (2-, 4-6-trimethylphenyl)) -, -C (= N- (2-, 6-dimethylphenyl)) -, -C (= N- (2-, 6-diethylphenyl)) -, -C (= N- (2-methyl-phenyl)) -, -C (= N- (2-ethylphenyl)) -, -C (= N- (2-trifluoromethylphenyl)) -, -C (= N- (2-isopropylphenyl)) -, -C (= N-phenyl) -, -C (= N- (naphthyl) - or -C (= 0) -, -CH2-, or R3, R5, R6 = H, R4 = 0Me, R1 = CN, - (X (R2) m.) M- represents a single bond, and - (Y (R7) n ') n- represents -C (= O) -, or R3, R4, R6 = H, R5 = OMe, Rl = CN, - (X (R2) m.) M- represents a single bond, and - (Y (R7) n.) N- represents -C (= 0) -, or R3, R4, R5, R6 = H, R1 = NH2, - (X (R2) m-) m- represents a single bond, and - (Y (R7) n-) n -represents -CH2- or -CH2-CH2-, or R3, R4, R5, R6 = H, R1 = NH2, - (X (R2) m.) M- represents -CH2- or -CH2-CH2- and - (Y (R7) n .-) n -represents a single bond. Preferably, the compound of the invention is defined as above, preferably with the exception of compounds where: R3, R4, R5, R6 = H, R1 = CN, - (X (R2) m.) M - represents a single bond, and - (Y (R7) n <) n- represents -C (= N- (2-, 4-, 6-trimethylphenyl)) -, -C (= N- (2-, 6-dimethylphenyl)) - , -C (= N- (2-, 6-diethylphenyl)) -, -C (= N- (2-methylphenyl)) -, -C (= N- (2-ethyl-phenyl)) -C ( = N- (2-trifluoromethylphenyl)) -, -C (= N- (2-iso-propylphenyl)) -, -C (= N-phenyl) -, -C (= N- (naphthyl) - or -C (= 0) -, -CH2-, or R3, R5, R6 = H, R4 = 0Me, RI = CN, - (x (R2) m.) M- represents a single bond, and - (Y (R7) n.) n- represents -C (= 0) -, or R3, R4, R6 = H, R5 = OMe, RI = CN, - (X (R2) m.) m- represents a single bond, and - ( Y (R7) npn- represents -C (= 0) -, or R3, R4, R5, R6 = H, R1 = NH2, - (X (R2) mpm- represents a single bond, and - (Y (R7) n.) - represents -CH2-, or R3, R4, R5, R6 = H, R1 = NH2, - (X (R2) m.) m- represents -CH2- and - (Y (R7) n.) n - represents a single bond Preferably, R1 is chosen from the group consists of H, CN, Hal, OAlq, OH, NRCN, C (CN) = C (OH) (OAlq), SR, NRRY C (0) NRRp Heterocycle, wherein Alk is optionally substituted by OAlq and where Heterocycle is optionally substituted by Hal. Preferably, R3, R4, R5, R6 are each identical or different and are independently selected from the group consisting of H, OAlq, OH, Alk, Hal. Preferably, - (Y (R7) n <) n - is a single bond or Y represents a carbon atom or an S atom. Preferably, - (X (R2) m-) m - represents a single bond. Preferably, R2 is selected from the group consisting of H, O. Preferably, R7 is selected from the group consisting of H, O, OH, N-OH, N-OAlq, N-Aryl, NO-Aryl or NO-Alk-Aryl, NO-Alk-Oaryl, NO-Alk-CO- (NR-Alq-CO) p-OAlq , NO-Alk-CO (NR-Alq-CO) p-OH, N-NR-CO-NRRY NO-CO-Alk or 2 R7 are bonded to it and together with Y form a heterocycle, where p 'is O or 1.

Preferably, R and R 'are each identical or different and are independently chosen from the group consisting of H, Alk. More preferably, in the formula (I), - (X (R2) m-) - represents a single bond, n is 1, n 'is 1, Y is a carbon atom; R1 is selected from the group consisting of H, CN, Hal, OAlq, OH, NRCN, C (CN) = C (OH) (OAlq), SR, NRRY C (0) NRRY Heterocycle, where Alk is optionally substituted by OAlq and where Heterocycle is optionally substituted by Hal; R3, R4, R5, R6 are each identical or different and are independently selected from the group consisting of H, OAlq, OH, Alk, Hal; R7 is selected from the group consisting of O, N-OH, N-OAlq, N-Aryl, N-O-Aryl or N-O-Alk-Aryl; R and R 'are each identical or different and are independently chosen from the group consisting of H, Alk; or their pharmaceutically acceptable salts, hydrates, or hydrated salts, or polymorphic crystalline structures of these compounds or their optical isomers, racemates, diastereomers or enantiomers. The preferred compounds of the invention are selected from the group consisting of: 9-hydroxy-3-methoxy-9H-indene [1,2-b] pyrazine-2-carbonitrile 3-methoxy-9-oxo-9H-indene [1 , 2-b] pyrazine-2-carbonitrile 3-dimethylamino-9-oxo-9H-indene [1,2-b] pyrazine-2-carbonitrile 3- (2-methoxy-ethoxy) -9-oxo-9H-indene [1, 2-b] pyrazine-2-carbonitrile 3-hydroxy-9-oxo-9H-indene [1,2-b] pyrazine-2-carbonitrile 3-amino-9-oxo-9H-indene [1, 2 -b] pyrazine-2-carbonitrile 3- (4, 4-difluoro-piperidin-1-yl) -9-oxo-9H-indene [1,2-b] pyrazine-2-carbonitrile 3-chloro-9-oxo -9H-indeno [l, 2-b] pyrazine-2-carbonitrile 9- (1 3'-dioxolan-2'-yl) -9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile Amide 2-cyano-9- [hydroxyimino] -9H-indene [1,2-b] pyrazine-3-carboxylic acid 9- (methoxyimino) -9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile - (allyloxyimino) -9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 9-Benzyloxyimino-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 9-Ethoxyimino-9H-indene [l, 2-b] pyrazine a-2, 3-dicarbonitrile 9-phenoxyimino-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 6-methoxy-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 6 , 7-Dimethoxy-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 8-Methyl-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 7,8-dimethoxy-9H -indeno [1,2-b] pyrazine-2,3-dicarbonitrile 6-Methyl-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 5,8-dimethoxy-9H-indene [1,2] -b] pyrazine-2,3-dicarbonitrile 6-methoxy-9-oxo-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 6, 7-dimethoxy-9-oxo-9H-indene [1 , 2-b] pyrazine-2,3-dicarbonitrile 8-Methyl-9-oxo-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 7,8-dimethoxy-9-oxo-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 6-Methyl-9-oxo-9H-indene. { l, 2-b] pyrazine-2,3-dicarbonitrile 5,8-dimethoxy-9-oxo-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 7-chloro-9-oxo-9H- indeno [1,2-b] pyrazine-2,3-dicarbonitrile 7-Fluoro-9-oxo-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 7-Hydroxy-9-oxo-9H- indeno [l, 2-b] pyrazine-2,3-dicarbonitrile benzo [4,5] thieno [2,3-b] pyrazine-2,3-dicarbonitrile 5,10-dioxo-5,10-dihydro-benzo [ g] quinoxaline-2,3-dicarbonitrile 9- [hydroxyimino] -9H-indene [l, 2-b] pyrazine-2,3-dicarbonitrile 2-cyano-9-oxo-9H-indene [1,2-b] pyrazin-3-yl-cyanamide 3- (l-cyano-2-ethoxy-2- hydroxy-vinyl) -9-oxo-9H-indene [1,2-b] pyrazine-2-carbonitrile 3-ethylsulfanyl-9-oxo-9H-indene [1,2-b] pyrazine-2-carbonitrile 7-Chloro -9-methoxyimino-9-H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 9-Allyloxyimino-7-chloro-9H-indene [1,2- b] pyrazine-2,3-dicarbonitrile 6 -Chloro-9-oxo-9H-indeno [1,2-b] pyrazine-2,3-dicarbonitrile 2- (2-cyano-9-oxo-9H-indeno [1,2-b] pyrazin-3-yl ) -acetamide 9- (2-phenoxy-ethoxyimino) -9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 7-chloro-9- (2-phenoxy-ethoxyimino) -9H-indene [1, 2-b] pyrazine-2,3-dicarbonitrile 9-Allyloxyimino-6-chloro-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 7-Fluoro-8-methyl-9-oxo-9H- indeno [1,2-b] pyrazine-2,3-dicarbonitrile 6, 7-dichloro-9-oxo-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 6-ethyl-9-oxo- 9H-indeno [1,2-b] pyrazine-2, 3-dicarbonitrile 2-cyano-9- [hydroxyimino] -9H-indene [1,2-b] -pyridine amide azine-3-carboxylic acid 9-Allyloxyimino-2-cyano-9H-indene [1,2-b]? irazine-3-carboxylic acid amide 2-cyano-9-ethoxyimino-9H-indene [l, 2- b] 2-Cyano-9- (2-methoxy-ethoxyimino) -9H-indene [1,2-b] pyrazine-3-carboxylic acid amide of 2-cyano-9-methoxyimino-2-cyano-9-carboxylic acid amide 9H-indeno [l, 2-b] pyrazine-3-carboxylic acid amide of 2-cyano-9-acetoxyimino-9H-indene [1,2-b] pyrazine-3-carboxylic acid amide of 2-cyano-9- oxo-9H-indeno [1,2-b] pyrazine-3-carboxylic acid ester of (3-carbamoyl-2-cyano-indene [1,2- b] pyrazin-9-ylideneaminoxy) -acetic acid ( 3-carbamoyl-2-cyano-indene [1, 2-b] pyrazin-9-ylideneaminoxy) -acetic acid ester of [2- (3-carbamoyl-2-cyano-indene [1,2-b] pyrazine] -9-ylidenaminoxy) -acetylamino] -acetic acid [2- (3-carbamoyl-2-cyano-indene [1,2-b] pyrazin-9-ylideneaminoxy) -acetylamino] -acetic acid 7-chloro-3-hydroxy -9-oxo-9H-indeno [1,2-b] pyrazine-2-carbonitrile 9- [(aminocarbonyl) hydrazone ] -7-chloro-9H-indene [l, 2-b] pyrazine-2,3-dicarbonitrile or its pharmaceutically acceptable salts, hydrates, or hydrated salts, or polymorphic crystalline structures of these compounds or their optical isomers, racemates, diastereomers or enantiomers. According to another aspect, the preferred compounds of the invention are selected from the group consisting of: 9-hydroxy-3-methoxy-9H-indene [1,2-b] pyrazine-2-carbonitrile 3-methoxy-9-oxo -9H-indeno [1,2-b] pyrazine-2-carbonitrile 3-dimethylamino-9-oxo-9H-indene [1,2-b] pyrazine-2-carbonitrile 3- (2-methoxy-ethoxy) -9 -oxo-9H-indene [1,2-b] pyrazine-2-carbonitrile 3-hydroxy-9-oxo-9H-indene [1,2-b] pyrazine-2-carbonitrile 3-amino-9-oxo-9H -indeno [1,2-b] pyrazine-2-carbonitrile 3- (4, 4-difluoro-piperidin-1-yl) -9-oxo-9H-indene [1,2-b] pyrazine-2-carbonitrile 3 -chloro-9-oxo-9H-indeno [1,2-b] pyrazine-2-carbonitrile 9- (1 ', 3'-dioxolan-2'-yl) -9H-indene [1,2-b] - pyrazine-2, 3-dicarbonitrile 2-cyano-9- [hydroxyimino] -9H-indene [1,2-b] pyrazine-3-carboxylic acid 9- (methoxyimino) -9H-indene [1, 2-b] ] pyrazine-2,3-dicarbonitrile 9- (allyloxyimino) -9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 9-benzyloxyimino-9H-indene [1,2-b] pyrazine-2, 3 -dicarbonitrile 9-Etoxii mino-9H-indeno [1,2-b] pyrazine-2,3-dicarbonitrile 9-phenoxyimino-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 6-methoxy-9H-indene [1, 2-b] pyrazine-2,3-dicarbonitrile 6, 7-dimethoxy-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 8-Methyl-9H-indene [1,2-b] pyrazine- 2,3-dicarbonitrile 7,8-dimethoxy-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 6-Methyl-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 8-Dimethoxy-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 6-methoxy-9-oxo-9H-indene [1,2- b] pyrazine-2,3-dicarbonitrile 6.7 -Dimethoxy-9-oxo-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 8-Methyl-9-oxo-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 7 , 8-Dimethoxy-9-oxo-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 6-Methyl-9-oxo-9H-indene [1,2-b] pyrazine-2, 3-dicarbonitrile 5,8-dimethoxy-9-oxo-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 7-chloro-9-oxo-9H-indene [1,2-b] pyrazine -2, 3-dicarbonitrile 7-Fluoro-9-oxo-9H-indeno [1,2-b] pyrazine-2,3-dicarbonitrile 7-Hydroxy-9-oxo-9H-indene [1,2-b] pyrazine -2, 3-dicarbonitrile benzo [4,5] thieno [2,3-b] pyrazine-2,3-dicarbonitrile 5,10-dioxo-5,10-dihydro-benzo [g] quinoxaline-2,3-dicarbonitrile 2-cyano-9-oxo-9H-indene [1,2-b] pyrazin-3-yl-cyanamide 3- (l-cyano-2-ethoxy-2-hydroxy-vinyl) -9-oxo-9H-indene [1, 2-b] pyrazine-2-carbonitrile 3-ethylsulfanyl-9-oxo-9H-indene [1,2-b] pyrazine-2-carbonitrile 7-Chloro-9-methoxyimino-9H-indene [1, 2 -b] pyrazine-2,3-dicarbonitrile 9-Allyloxyimino-7-chloro-9H-indene [1,2-b] -pyrazine-2,3-dicarbonitrile 6-chloro-9-oxo-9H-indene [1, 2-b] pyrazine-2,3-dicarbonitrile 2- (2-cyano-9-oxo-9H-indene { 1, 2-b] pyrazin-3-yl) -acetamide 9- (2-Phenoxy-ethoxyimino) -9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 7-Chloro-9- (2-phenoxy-ethoxyimino) -9H-indene [1,2-b] ] pyrazine-2,3-dicarbonitrile 9-Allyloxyimino-6-chloro-9H-indene [1,2-b] -pyrazine-2,3-dicarbonitrile 7-Fluoro-8-methyl-9-oxo-9H-indene [ 1, 2-b] pyrazine-2,3-dicarbonitrile 6, 7-dichloro-9-oxo-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 6-ethyl-9-oxo-9H- indene [1,2-b] pyrazine-2, 3-dicarbonitrile 2-cyano-9- [hydroxyimino] -9H-indene [1,2-b] pyrazine-3-carboxylic acid 9-Allyloxyimino-2-acid cyano-9H-indeno [l, 2-b] pyrazine-3-carboxylic acid amide 2-Cyano-9-ethoxyimino-9H-indene [1,2-b] pyrazine-3-carboxylic acid amide of 2-Cyanic acid -9- (2-methoxy-ethoxyimino) -9H-indene [1,2-b] pyrazine-3-carboxylic acid amide of 2-cyano-9-methoxyimino-9H-indene [1,2-b] pyrazine-3 -carboxylic acid amide of 2-cyano-9-acetoxyimino-9H-indene [1,2-b] pyrazine-3-carboxylic acid amide of 2-cyano-9-oxo-9H-indene. { l, 2-b] pyrazine-3-carboxylic acid ester of (3-carbamoyl-2-cyano-indene [1,2- b] pyrazin-9-ylideneaminoxy) -acetic acid (3-carbamoyl-2-) cyano-indeno [l, 2-b] pyrazin-9-ylideneaminoxy) -acetic acid ester of [2- (3-carbamoyl-2-cyano-indene [1,2-b] pyrazin-9-ylideneaminoxy) - acetylamino] -acetic acid of [2- (3-carbamoyl-2-cyano-indene [1,2-b] pyrazin-9-ylideneaminoxy) -acetylamino] -acetic acid 7-chloro-3-hydroxy-9-oxo-9H -indeno [1, 2-b] pyrazine-2-carbonitrile 9 - [(aminocarbonyl) hydrazono] -7-chloro-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile or its pharmaceutically acceptable salts, hydrates, or hydrated salts, or polymorphic crystalline structures of these compounds or their optical isomers, racemates, diastereomers or enantiomers. More preferably, the compounds of the invention are selected from the group consisting of: 2-cyano-9- [hydroxyimino] -9H-indene [1,2-b] pyrazine-3-carboxylic acid amide 9- (methoxyimino) -9H -indeno [l, 2-b] pyrazine-2,3-dicarbonitrile 9-Benzyloxyimino-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile (13c). 9-Ethoxyimino-9H-indeno [1,2-b] pyrazine-2,3-dicarbonitrile (13d). 9-Phenoxyimino-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile (13e). 8-Methyl-9-oxo-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 6-Methyl-9-oxo-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile , 8-Dimethoxy-9-oxo-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 7-chloro-9-oxo-9H-indene [1,2-b] pyrazine-2, 3 -dicarbonitrile 7-Fluoro-9-oxo-9H-indeno [1,2-b] pyrazine-2,3-dicarbonitrile 2-cyano-9-oxo-9H-indene [1,2-b] pyrazine-3-amide carboxylic or its pharmaceutically acceptable salts, hydrates, or hydrated salts, or polymorphic crystalline structures of these compounds or their optical isomers, racemates, diastereomers or enantiomers. In accordance with a further objective, the present invention also relates to pharmaceutical compositions comprising a compound of the formula (I) (l) where: m is 0; 1 or 2, where when m = 0, - (X (R2) mpm is none, so that it forms an open ring or a single bond, n is 0, 1 or 2,, where when n = 0, (Y (R7) n.) N is none, so that it forms an open ring or a single bond, m 'and n' are independently 0, 1 or 2, X is a carbon atom or S or N; Y is a carbon atom, or S or N; With the proviso that m and n are not simultaneously 0; it is either a double or simple link, as appropriate; it is either none or a simple link, as appropriate; R1 is selected from the group consisting of H, CN, Hal, OAlq, OH, NRCN, C (CN) = C (OH) (OAlq), SR, NRRY (Alq) pC (O) NRR ', Heterocycle, Aryl, Heteroaryl, where Alk, Aryl, Heteroaryl, Heterocycle are optionally substituted by Hal, NRRY CN, OH, CF3, Aryl, Heteroaryl, OAlq Where p is 0 or 1; R3, R4, R5, R6 are each identical or different and are independently selected from the group consisting of H, OAlq, Alk, Hal, NRRY CN, OH, CF3, Aryl, Heteroaryl; R2 is selected from the group consisting of H, O, OH, N-OH, N-Aryl, N-OAlq, N-O-Aryl, NO-Alk-Aryl, N-NR-CONRRY NO-CO-Alk, or 2 R2 is linked to the same X is formed together with X a heterocycle; wherein the Alk, Aryl or heterocycle are optionally substituted by OAlk, Alk, Hal, NRRYCN, OH, CF3, OAril, -CO- (NR-Alq-CO) p-OAlq, -CO (NR-Alq-CO ) p-OH, where p 'is O or 1; R7 is selected from the group consisting of H, O, OH, N-OH, N-Aryl, N-OAlq, N-O-Aryl, NO-Alk-Aryl, N-NR-CONRRY NO-CO- Alk, or 2 R7 is linked to the same Y and a heterocycle is formed together with Y; wherein the Alkyl, Aryl or heterocycle are optionally substituted by OAlk, Alk, Hal, NRRYCN, OH, CF3, OAril, -CO- (NR-Alq-CO) p.-OAlq, -CO (NR-Alk-CO ) P-OH, where p 'is 0 or 1; R and R 'are each identical or different and are independently chosen from the group consisting of H, Alk, wherein Alk is optionally substituted by Hal, NRRY CNi OH, CF3, Aryl, Heteroaryl; or their pharmaceutically acceptable salts, hydrates, or hydrated salts, or polymorphic crystalline structures of these compounds or their optical isomers, racemates, diastereomers or enantiomers. According to a still further objective, the present invention relates to the use of a compound of the formula (1) as defined with respect to the pharmaceutical compositions of the invention, for the preparation of a medicament for inhibiting the cysteine protease. Preferred embodiments of the formula (I) for the pharmaceutical compositions and use of the invention are defined as above. Preferred compounds for the pharmaceutical compositions and use of the invention are chosen from the group consisting of: 9-oxo-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 9-hydroxy-3-methoxy-9H -indeno [l, 2-b] pyrazine-2-carbonitrile 3-methoxy-9-oxo-9H-indene [1,2-b] pyrazine-2-carbonitrile 3-dimethylamino-9-oxo-9H-indene [l , 2-b] pyrazine-2-carbonitrile 3- (2-methoxy-ethoxy) -9-oxo-9H-indene. [1,2-b] pyrazine-2-carbonitrile 3-hydroxy-9-oxo-9H- indeno [l, 2-b] pyrazine-2-carbonitrile 3-amino-9-oxo-9H-indene [1,2-b] pyrazine-2-carbonitrile 3- (4, 4-difluoro-piperidin-1-yl ) -9-oxo-9H-indene [1,2-b] pyrazine-2-carbonitrile 3-chloro-9-oxo-9H-indene [1,2- b] pyrazine-2-carbonitrile 9- (1 ', 3'-dioxolan-2'-yl) -9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 2-cyano-9- [hydroxyimino] -9H-indene [1, 2-b] amide ] pyrazine-3-carboxylic acid 9- [hydroxyimino] -9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 9- (methoxyimino) -9H-indeno [1,2-b] pyrazine-2, 3 -dicarbonitrile 9- (allyloxyimino) -9H -indeno [l, 2-b] pyrazine-2,3-dicarbonitrile 9-Benzyloxyimino-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 9-Ethoxyimino-9H-indene [1,2-b] ] pyrazine-2, 3-dicarbonitrile 9-Phenoxyimino-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 9- [Phenylimino] -9H-indeno [1,2-b] pyrazine-2,3-dicarbonitrile 6-Methoxy-9H-indene. { 1, 2-b] pyrazine-2,3-dicarbonitrile 6, 7-dimethoxy-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 8-Methyl-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 7,8-dimethoxy-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 6-methyl-9H-indene [1,2- b] pyrazine-2, 3- dicarbonitrile 5,8-dimethoxy-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 6-methoxy-9-oxo-9H-indene [1,2- b] pyrazine-2,3-dicarbonitrile 6 , 7-Dimethoxy-9-oxo-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 8-Methyl-9-oxo-9H-indene [1,2-b] pyrazine-2, 3 -dicarbonitrile 7,8-Dimethoxy-9-oxo-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 6-Methyl-9-oxo-9H-indene [1,2-b] pyrazine-2 , 3-dicarbonitrile 5,8-dimethoxy-9-oxo-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 7-chloro-9-oxo-9H-indene [1,2-b] pyrazine -2, 3-dicarbonitrile 7-Fluoro-9-oxo-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 7-Methoxy-9-oxo-9H-indene [1,2-b] pyrazine -2,3-dicarbonitrile 7-Hydroxy-9-oxo-9H ~ indeno [1,2-b] pyrazine-2,3-dicarbonitrile benzo [4, 5] t ieno [2, 3-b] pyrazine-2,3-dicarbonitrile 5, 10-dioxo-5, 10-dihydro-benzo [g] quinoxaline-2,3-dicarbonitrile 2-cyano-9-oxo-9H-indene [ l, 2-b] pyrazin-3-yl-cyanamide 3- (l-cyano-2-ethoxy-2-hydroxy-vinyl) -9-oxo-9H-indene [1,2-b] pyrazine-2-carbonitrile 3-Ethylsulfanyl-9-oxo-9H-indene [1,2-b] pyrazine-2-carbonitrile 7-Chloro-9-methoxyimino-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 9- Allyloxyimino-7-chloro-9H-indene [1,2-b] -pyrazine-2,3-dicarbonitrile 6-chloro-9-oxo-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 2- (2-cyano-9-oxo-9H-indeno [1,2- b] pyrazin-3-yl) -acetamide 9- (2-Phenoxy-ethoxyimino) -9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 7-Chloro-9- (2-phenoxy-ethoxyimino) -9H-indene [1, 2-b] ] pyrazine-2, 3-dicarbonitrile 9-Allyloxyimino-6-chloro-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 7-Fluoro-8-methyl-9-oxo-9H-indene [l , 2-b] pyrazine-2,3-dicarbonitrile 6, 7-dichloro-9-oxo-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 6-ethyl-9-oxo-9H-indene [1,2-b] pyrazine-2, 3-dicarbonitrile 2-cyano-9- [hydroxyimino] -9H-indene [1,2-b] pyrazine-3-carboxylic acid 9-Allyloxyimino-2-cyano acid amide -9H-indeno [1,2-b] pyrazine-3-carboxylic acid amide 2-Cyano-9-ethoxyimino-9H-indene [1,2-b] pyrazine-3-carboxylic acid amide of 2-Cyano- 9- (2-methoxy-ethoxyimino) -9H-indene [1,2-b] pyrazine-3-carboxylic acid 2-cyano-9-methoxyimino-9H-indene [1,2-b] pyrazine-3-amide carboxylic acid amide of 2-cyano-9-acetoxyimino-9H-indene [1,2-b] pyrazine-3-carboxylic acid amide of 2-cyano-9-oxo-9H-indene [1,2-b] pyrazine- 3-carboxylic ethyl ester of (3-carbamoyl-2-cyano-indene [1,2-b] pyrazin-9-ylideneaminoxy) -acetic acid (3-carbamoyl-2-cyano-indene) acid. { 1, 2-b] pyrazin-9-ylideneaminoxy) -acetic acid [2- (3-carbamoyl-2-cyano-indene [1,2-b] pyrazin-9-ylideneaminoxy) -acetylamino] -acetic acid ethyl ester [2- (3-carbamoyl-2-cyano-indene [1, 2-b] pyrazin-9-ylideneaminoxy) -acetylamino] -acetic acid 7-chloro-3-hydroxy-9-oxo-9H-indene [1] , 2-b] pyrazine-2-carbonitrile 9 - [(aminocarbonyl) hydrazono] -7-chloro-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile or its pharmaceutically acceptable salts, hydrates, or salts hydrated, or polymorphic crystalline structures of these compounds or their optical isomers, racemates, diastereomers or enantiomers. The most preferred compounds for the pharmaceutically composition and use of the invention are selected from the group consisting of: 9-oxo-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 2-cyano-9-amide - [hydroxyimino] -9H-indeno [1,2-b] pyrazine-3-carboxylic acid 9- (methoxyimino) -9H-indeno [1,2-b] pyrazine-2,3-dicarbonitrile 9-Benzyloxyimino-9H-indene [L, 2-b] pyrazine-2,3-dicarbonitrile (13c). 9-Ethoxyimino-9H-indeno [1,2-b] pyrazine-2,3-dicarbonitrile (13d). 9-Phenoxyimino-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile (13e). 9- [Phenylimino] -9H-indeno [1,2-b] pyrazine-2,3-dicarbonitrile 8-Methyl-9-oxo-9H-indene [1,2- b] pyrazine-2,3-dicarbonitrile 6-Methyl-9-oxo-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile , 8-Dimethoxy-9-oxo-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 7-chloro-9-oxo-9H-indene [1,2-b] pyrazine-2, 3 -dicarbonitrile 7-Fluoro-9-oxo-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 2-cyano-9-oxo-9H-indene [1,2-b] pyrazine-2-dicarbonitrile 3-carboxylic acid or its pharmaceutically acceptable salts, hydrates or hydrated salts, or the polymorphic crystalline structures of these compounds or their optical isomers, racemates, diastereomers or enantiomers. As used herein before or after: Alk represents alkyl, alkene or alkyne. "Alkyl" means a group of aliphatic hydrocarbons which may be linear or branched having 1 to 20 carbon atoms in the chain. Preferred alkyl groups have 1 to 12 carbon atoms in the chain. "Branched" means that one or more lower alkyl groups such as methyl, ethyl, or propyl are linked to a straight chain. Exemplary alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, 3-pentyl, octyl, nonyl, decyl. "Alkene" means a group of aliphatic hydrocarbons containing a carbon-carbon double bond and which may be linear or branched having 2 to 15 carbon atoms in the chain. Preferred alkenyl groups have 2 to 12 carbon atoms in the chain; and more preferably about 2 to 4 carbon atoms in the chain. Exemplary alkenyl groups include ethenyl, propenyl, n-butenyl, i-butenyl, 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl, nonenyl, decenyl. "Alkyne" means a group of aliphatic hydrocarbons containing a triple carbon-carbon bond and which may be linear or branched having 2 to 15 carbon atoms in the chain. The preferred alkynyl groups have 2 haeta 12 carbon atoms in the chain; and more preferably 2 to 4 carbon atoms in the chain. Exemplary alkynyl groups include ethynyl, propynyl, n-butynyl, 2-butynyl, 3-methylbutynyl, n-pentynyl, heptynyl, octynyl and decynyl. "Halogen atom" refers to fluorine, chlorine, bromine or iodine atom; preferably fluorine and chlorine atoms. "Aryl" means an aromatic monocyclic or multicyclic hydrocarbon ring system of 6 to 14 carbon atoms, preferably 6 to 10 carbon atoms. Exemplary aryl groups include phenyl or naphthyl. As used herein, the terms "heterocycle" or "heterocyclic" refer to mono, bi or multicyclic rings of 5 to 10 members, non-aromatic stable 3 to 14, partially unsaturated or unsaturated, saturated where at least a member of the ring is a hetero atom. Typically, heteroatoms include, but are not limited to, oxygen, nitrogen, sulfur, selenium, and phosphorus atoms. The preferred heteroatoms are oxygen, nitrogen and sulfur. Suitable heterocycles are also described in The Handbook of Chemistry and Physics, 76th Edition, CRC Press, Inc., 1995-1996, p. 2-25 to 2-26, the description of which is incorporated herein by reference. Preferred non-aromatic heterocyclics include, but are not limited to pyrrolidinyl, pyrazolidinyl, imidazoiidinyl, oxiranyl, tetrahydrofuranyl, dioxolanyl, tetrahydro-pyranyl, dioxanyl, dioxolanyl, piperidyl, piperazinyl, morpholinyl, pyranyl, imidazolinyl, pyrrolinyl, pyrazolinyl, thiazolidinyl, tetrahydrothiopyranyl, dithianyl, thiomorpholinyl, dihydro-pyranyl, tetrahydropyranyl, dihydropyranyl, tetrahydro-pyridyl, dihydropyridyl, tetrahydropyrinidinyl, dihydrothiopyranyl, azepanyl, as well as the fused systems resulting from condensation with a phenyl group.

As used herein, the term "heteroaryl" or aromatic heterocycles refers to a hetero, mono, bi or multicyclic aromatic ring of 5 to 10 members, preferably 5 members of 14 members. Examples include pyrrolyl, pyridyl, pyrazolyl, thienyl, pyrimidinyl, pyrazinyl, tetrazolyl, indolyl, quinolinyl, purinyl, imidazolyl, thienyl, thiazolyl, benzothiazolyl, furanyl, benzofuranyl, 1,2,4-thiadiazolyl, isothiazolyl, triazoyl, tetrazolyl, isoquinolyl, benzothienyl, orobenzofuryl , pyrazolyl, carbazolyl, benzimidazolyl, isoxazolyl, pyridyl-N-oxide, as well as the fused systems resulting from the condensation with a phenyl group. "Alkyl", "cycloalkyl", "alkenyl", "alkynyl", "aryl", "heteroaryl", "heterocycle" and the like also refer to the corresponding "alkylene", "cycloalkylene", "alkenylene", "alkynylene" , "arylene", "heteroarylene", "heterocycle" and the like which are formed by the removal of two hydrogen atoms. As used herein, the term "patient" refers to either an animal, such as a valuable animal for breeding, companion or conservation purposes or preferably a human or human child, which suffers or has the potential to suffer one or more diseases and conditions described herein. As used herein, "a therapeutically effective amount" refers to an amount of a compound of the present invention which is effective in preventing, reducing, eliminating, treating or controlling the symptoms of the diseases and conditions described in the foregoing. . The term "control" is understood to refer to all purposes where it may decrease, interrupt, arrest, or stop the progression of the disease and conditions described herein, but not necessarily indicate a total elimination of all diseases and symptoms of the disease. the condition and it is understood to include prophylactic treatment. As used herein, the term "pharmaceutically acceptable" refers to these compounds, materials, excipients, compositions or dosage forms which are within the scope of medical judgment, suitable for contacting the tissues of humans and animals. no excess toxicity, irritation, allergic reepheta, or other complication problems in proportion to a range of benefit / risk. As stated in the preamble, "pharmaceutically acceptable salts" refer to derivatives of the described compounds wherein the precursor compound is modified by making acid or base salts thereof. Pharmaceutically acceptable saltse include conventional non-toxic lae ealee or quaternary ammonium salts of the parent compound formed, for example, from non-toxic organic or inorganic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and eimilar, and saltse prepared from organic acids such as acetic, propionic, euccinic, tartaric, citric, methanesulfonic , benzeneulfonic, glucuronic, glutamic, benzoic, ealicyclic, toluene sulfonic, oxalic, fumaric, lactic and the like. The addition salts further include ammonium salts such as tromethamine, meglumine, epolamine, etc., metal salts such as sodium, potassium, calcium, zinc or magnesium. The pharmaceutically acceptable salts of the present invention can be synthesized from the precursor compound which contains a basic or acid portion by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Science, 17h ed., Mack Publishing Company, Easton, PAi 1985, p. 1418, the description of which is incorporated herein by reference. The compounds of the general formula (I) have geometries and etheretomers are also a part of the invention. According to an additional object, the present invention is also referred to the processes of the preparation of the compounds of the formula (I). The compounds and processes of the present invention can be prepared in a number of ways well known to those skilled in the art. The compounds can be synthesized, for example, by application or adaptation of the methods described below, or variations thereof as appreciated by one of skill in the art. Appropriate modifications and substitutions will be readily apparent and well known or easily obtained from the scientific literature by those skilled in the art. In particular, such methods can be found in R.C. Larock, Comprehensive Organic Transformations, Wiley-VCH Publiehere, 1999. It will be appreciated that the compounds of the present invention may contain one or more asymmetrically sub-substituted carbon atoms, and may be isolated in optically active or racemic forms. Thus, all chiral, diastereomeric, racemic forms and all isomeric geometric forms of a structure are intended, unless the specific stereochemical or isomeric form is specifically indicated. It is known in the art how to prepare and isolate such optically active forms. For example, mixtures of ether stereoisomers can be separated by standard techniques including, but not limited to, resolution of racemic, normal, reverse phase and chiral chromatography forms, preferential salt formation, recrystallization and the like, or by chirality and material matter. starting chiral or deliberately by the objective chiral centers.

The compounds of the present invention can be prepared by a variety of synthetic routes. The reactants and starting materials are commercially available or facilitate the synthesis by techniques well known to one of skill in the art. All substituents unless indicated otherwise, are as previously defined. In the reactions described hereinafter, it may be necessary to protect the reactive functional groups, for example, hydroxy, amino, imino, thio or carboxy groups, where groups are desired in the final product, to avoid unsuitable participation in the reaction. . The group of conventional protectants can be used in accordance with standard practice, for example, see T. W. -Greene and P.M. Wuts in Protective Groups in Organic Chemistry, 3rd ed. , John Wiley and Sons, 1999; J. F. W. McOmie in Protective Groups in Organic Chemistry, Plenum Prese, 1973. Some reactions can be carried out in the presence of a base. There is no particular restriction on the nature of the base to be used in this reaction, and any base conventionally used in reactions of this type can also be used in the present, providing that it has no adverse effect on other parts of the molecule. Examples of suitable bases include: sodium hydroxide, potassium carbonate, triethylamine, alkali metal hydrides, such as sodium hydride and potassium hydride; alkyllithium compounds, such as methyllithium and butyllithium; and alkali metal alkoxide, such as sodium methoxide and sodium ethoxide. Usually, the reactions are carried out in a suitable solvent. A variety of solvents can be used, with the proviso that there is no adverse effect in the reaction or in the reagents involved. Examples of suitable solvents include: hydrocarbons, which may be aromatic, aliphatic or cycloaliphatic hydrocarbons, such as hexane, cyclohexane, benzene, toluene and xylene; amides, such as dimethylformamide; alcohol talee as ethanol and methanol and ethereal, such as diethyl ether and tetrahydrofuran. The reactions can be carried out over a wide range of temperatures. In general, we find it convenient to carry out the reaction at a temperature from 0 ° C to 150 ° C (more preferably from about room temperature to 100 ° C). The time required for the reaction can also vary widely, depending on many factors, notably the reaction temperature and the nature of the reactants. However, with the condition that the reaction is effected under the preferred conditions summarized above, a period from 3 hours to 20 hours is usually sufficient. The compound thus prepared can be recovered from the reaction mixture by conventional means. For example, the compounds can be recovered by completely distilling the solvent from the reaction mixture or if necessary after the solvent is fully distilled from the reaction mixture, the residue is poured into water followed by extraction with a water-miscible organic solvent. and the extract solvent is completely distilled. Additionally, the product can also be purified by various well-known techniques, such recrystallization, reprecipitation or the various chromatography techniques, notably column chromatography or preparative thin layer chromatography. The process for preparing a compound of the formula (I) of the invention is a further object of the present invention. According to a first aspect, the compounds of the invention of the formula (I) can be obtained from the corresponding compounds of the formula (II) (ii) wherein R3, R4, R5, R6, X, Y, m, rrP, n, n 'are defined as in formula (I) and R7' ee R7 as defined in formula (I) or a precursor thereof and R1 'is R1 as defined in formula (I) or a precursor thereof. In accordance with the present invention, the term "precursor group" of a functional group refers to any group which can by one or more reactions reach the desired function, by means of one or more suitable reagents. These reactions include deprotection, as well as usual addition, substitution or functionalization reactions. Preferably, in formula (II), RV represents a CN group. Generally, the compound of the formula (I) is obtained from the compound of the formula (II) by one or more steps allowing the function to be transformed into the desired -R1 group. Simultaneously, the R7 'group can be transformed to R7 desired, if appropriate. The compounds of the formula (II) can be obtained from the corresponding compounds of the formula (III): (III) where R3, R4, R5, R6, X, Y, m,? T? ' , n, n 'are defined as in the formula (I) and R7' is defined as in the formula (II). Generally, when R1 '= CN, this reaction is usually carried out in the presence of diaminomalenedinitrile. According to an alternative embodiment, the compounds of the formula (II) can be obtained from the corresponding components of the formula (III): (III ') where R3, R4, R5, R6, X, Y, m, m', n, n 'ee are defined as in formula (I) and R7' ee defined as in the formula (IIIP - Generally, when R.sub.1 '= CN, this reaction is carried out in the presence of diaminomalenedinitrile According to an alternative embodiment, the compound of the formula (II) can be obtained from the corresponding compounds of the formula (IV): (IV), wherein R3, R4, R5, R6, X, Y, m, irT, n, n 'are defined as in formula (I) and R7"represents R7' or a precursor thereof, if The compound of the formula (III) can be obtained from a corresponding compound of the formula (V): (V) wherein R3, R4, R5, R6, X, Y, m, m1, n, n 'are defined as in the formula (I) and R7' is defined as in the formula (II). The compound of the formula (IV) can be obtained from a corresponding compound of the formula (III). Generally, this reaction is carried out in the presence of diaminomaleodinitrile. The reactions above can be carried out by the person skilled in applying or adapting the methods illustrated in the examples hereinafter. In addition, the processes of the invention may also comprise the additional step of lubricating the composition of formula (I). This can be done by the person of skill by any of the conventional means known, such as the recovery methods described above. The starting products are commercially available or can be obtained by applying or adapting any known method or those described in the examples. The synthesis can also be carried out in a container as a multicomponent reaction. According to a further object, the present invention also relates to pharmaceutical compositions comprising a compound of the formula (I) together with pharmaceutically acceptable excipients. The compounds of the invention are useful for inhibiting cysteine proteases, in particular deubiquitination enzymes (such as USP and UCH), caspaeae, cathepeins (in particular cathepsin B, D, K, S and the like), calpains, aei as cietein viral proteases, bacterial or parasitic in patients who need them. The compounds of the invention are particularly useful for treating and / or preventing cancer and metastasis, neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, deafness, disorders associated with aging, disorder and inflammation, arthritis, osteoporosis, hepatitic, hepatic inefficiency, leukemia. and cardiac inefficiency, stroke, atherosclerosis, kidney failure, diabetes, cataracts; acute or latent viral infections by Herpes simplex virus-1, Epstein-Barr virus, Coronavirus SARS, rhinovirus, poliovirus, hepatitis A virus, hepatitis C virus, adenovirus, and the like; bacterial or fungal infections by pathogenic agents that occur in the genus of the specie Streptococcus, Staphylococcus, Clostidium, Aspergillus, and the like; protozoalee infections by members of the species genera of Trypanosoma, Plasmodium, Leishmania, Trichomonas, Entamoeba, Giardia, Toxoplasma, Cryptosporidium, and the like; flat or roundworm infections by the members of the species of the genus of the eepecies Faeciola, Schistoeoma, Onchocerca, Ascaris, Taenia, Caenorhabi tis, Toxocara, Haemonchus, Ancylostoma, Trichuris, Trichinella, Strongyloidee, Brugia, and the like; as well as immunological disorders, immunoregulatory or presentation of antigens. The present invention also relates to the corresponding methods of treatment comprising the administration of a compound of the invention together with a pharmaceutically acceptable carrier or excipient to a patient in need thereof. The identification of those subjects who need treatment for diseases and disorders of the present are within the skill and knowledge of one of skill in the art. A veterinarian or a doctor of skill in the art can easily identify, by the use of clinical tests, physical examination, medical / family histories or biological and diagnostic tests, that they need to be treated. A therapeutically effective amount can easily be determined by the diagnostic personnel serving, as one of skill in the art, by the use of conventional techniques and by observing the result obtained under analogous circumstance. In determining the therapeutically effective amount, a number of factors are considered by the diagnostic personnel it serves, including, but not limited to: the subject's species: size, age, and general health; the specific disease involved; the degree of involvement or the severity of the disease; the response of the individual eujeto; the particular administration compound; the mode of administration; the characteristic bioavailability of the preparation administered; the dosie regime selected; the use of concomitant medication; and other relevant circumstances. The amount of a compound of the formula (I), which is required to carry out the desired biological effect, varies depending on a number of factors, including the chemical characteristics (e.g., hydrophobicity) of the compotetoe employed, the potency of the compounds, the type of disease, the species to which the patient belongs, the state of the patient's disease, the route of administration, the bioavailability of the compound by the chosen route, all the factors which dictate the amount of required doses, regimen and release to be administered. "Pharmaceutically" or "pharmaceutically acceptable" refers to molecular entities and compositions that do not produce an adrenergic, allergic or other adverse reaction when administered to an animal, or a human as appropriate. As used herein, "pharmaceutically acceptable excipient" includes carriers, diluents, adjuvants, or vehicles, such as prevention agents or antioxidants, fillers, disintegrating agents, wetting agents, emulsifying agents, drying agents, solvents, media, Disperesion, coatings, antibacterial and antifungal agents, isotonic delay and absorption agents and similaree. The use of drugs and agents for pharmaceutically active subetanciae is well known in the art. Except that any conventional means or agent is incompatible with the active ingredient, its use in therapeutic compositions is contemplated. The euplementary ingredients can also be incorporated into the compositions as suitable therapeutic combinations. In the context of the invention, the term "treaty" or "treatment", as used herein, means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which the term applies, or one or more symptoms of the disorder or condition.

"A therapeutically effective amount" means an amount of a compound / medicament according to the present invention effective in preventing or treating a pathological condition that requires the inhibition of an active cysteine protease involved in its pathogenesis. According to the invention, the term "patient", or "patient in need thereof", is designated for an animal or human that affects or is slightly affected with a pathological condition involving a cietein protease active in its pathogenesis. Preferably, the patient is human. In general terms, the compounds of this invention can be provided in a fieiologically aqueous buffer solution containing 0.1 haeta 10% w / v of the composition for parenteral administration. The typical doeie range is from 1 μg / kg to 0.1 g / kg of body weight per day; a preferred dosage range is from 0.01 mg / kg to 10 mg / kg of body weight per day or an equivalent dose in a human child. The preferred dose of the drug to be administered is probably dependent on such variables as type and extension of the progression of the disease or traitorno, the general health status of the particular patient, the relative biological efficacy of the selected compound, the formulation of the compote, the route of administration (intravenous, intramuscular, or other), the pharmacokinetic properties of the compound by the release route obtained and the speed (continuous infusion or bolus) and administration schedule (number of repetitions in a given period of time). The cartilates of the present invention are also capable of being administered in unit dose forms, where the term "unit dose" means a single dose which is capable of being administered to a patient, and which can be easily manipulated and packaged, subtracting as a physically and chemically stable unit dose comprising either the active compound itself or a pharmaceutically acceptable composition as described hereinafter. Such a serum, the total typical daily dose range is from 0.01 to 100 mg / kg of body weight. As a general guide, the unit dose for human ranges from 1 mg to 3000 mg per day. Preferably the unit dose range is from 1 haeta 500 mg administered one to six times per day and even more preferably from 10 mg to 500 mg, once per day. The compounds provided herein may be formulated into pharmaceutical compositions by mixing with one or more pharmaceutically acceptable excipients. Such unit dose compositions can be prepared or used by oral administration, particularly in the form of tablets, simple capsules or soft gel capsules; or intransally, particularly in the form of powders, nasolaye or aeroeolee drops; or derly, for example, topically in ointments, lotions, gels or sprays or by means of transdermal patches. The compositions may conveniently be administered in unit dosage form and may be prepared by any of the methods known in the pharmaceutical art, for example, as described in Remington: The Science and Practice of Pharmacy, 20th ed.; Gennaro, A. R., Ed .; Lippincott Williams & Wilkins: Philadelphia, PA, 2000. Preferred formulations include pharmaceutical compositions in which a compound of the present invention is formulated by oral or parenteral administration. For oral administration, tablets, pills, powders, capsules, troches, and the like may contain one or more of any of the following ingredients or compound of a similar nature: a binder such as microcrystalline cellulose, or gum tragacanth; a diluent such as starch or lactose; a disintegrant such a starch and cellulose derivatives; a lubricant such as magnesium stearate, a flow improver such as colloidal silicon dioxide; a sweetening agent such as eucroea or eacarina; or a flavoring agent such as mints, or methyl ealicylate. The capsules may be in the form of a hard capsule or soft capsule, which is generally made of mixtures of gelatins optionally mixed with plasticizers, as well as starch capsules. In addition, unit dosage forms may contain various other materials that modify the physical form of the dosage unit, for example, sugar coating, eeller, or enteric agent. Other forms of oral dosing such as syrups or elixirs may contain sweetening agents, preservatives, pigments, dyes, and flavorings. In addition, the active compounds can be incorporated into rapid dissolution, modified release or sustained release formulations and formulations, and wherein the sustained release formulations are preferably bi-modal. Preferred tablets contain lactose, corn starch, magnesium silicate, croscarmellose sodium, povidone, magnesium stearate, or talc in any combination. Liquid preparations for parenteral administration include sterile aqueous or nonaqueous solutions, ecutions, and emulsification. The liquid compositions may also include binders, buffer solutions, preservatives, chelating agents, sweeteners, flavorings and colorants, and the like. Non-aqueous solvents include alcohols, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and organic esters such as ethyl oleate. Aqueous carriers include mixtures of alcohols and water, buffering medium, and saline. In particular, biodegradable, biocompatible lactide polymers, lactide / glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers can be useful excipients for controlling the release of the active compounds. Intravenous vehicles can include fluid and nutrient replacements, electrolyte replacements, such as those based on Ringer's dextrose, and the like. Other potentially useful parenteral administration dosmas for active compounds include ethyl vinyl acetate ccpolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Alternative modes of administration include formulations for inhalation, including means such as dry powder, aeroeol, or drops. These can be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycolate and deoxycholate, or solvents for administration in the form of nasal drops, or as a gel for intransal application. Formulations for buccal administration include, for example, capsule or pills and may also include a flavored base, such as sucrose or acacia, and other excipients such as glycolate. Formulations suitable for rectal administration are preferably presented as unitary doeceitories, with a solid base carrier, such as cocoa butter, and may include a salicylate. Formulations for topical application to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil. The carriers that may be used include include petroleum jelly, polyethyl glycols, alcohols, or combinations thereof. Formulations suitable for transdermal administration may be presented as discrete patches and may be lipophilic or buffered emulsions, aqueous solutions, die or die-dried in a polymer or an adhesive. The invention is further illustrated but not restricted by the description in the following examples. The representative compounds of the invention are summarized in the table below: Formula No. of Experiment Example 1 Example 2 Example 3 Example 4 G- Example 5 YC Example 6 Example 7 Example 8 Example 9 25 10 15 20 Experiments The representative compounds of the invention can be synthesized according to the following procedures: Synthesis of 9-oxo-9H-indeno [1,2-b] pyrazin-2,3-dicarbonitrile (1): To a solution of ninhydrin (18.58 g, 104.3 mmol) in H2O / EtOH / AcOH (130: 195: 9.1, 167 mL) a solution of diaminomalenedinitrile (11.27 g, 104.3 mmol) in H20 / EtOH / AcOH (130: 195: 9.1; 167 ml) was added and the mixture was stirred at 60 ° C. After 3 hours, the precipitate was collected by filtration, washed with EtOH (100 ml) and dried under vacuum, yielding 1 (23.64 g, 98%) as a yellow-brown solid. X H NMR (300 MHz, CDCl 3): d 8.07 (d, 1 H), 7.98 (d, 1 H), 7.87 (dd, 1 H), 7.76 (dd, 1 H). ESI + MS: calculated for C? 3 H 4 N 40: 232.20; found: 233.0 (MH +).

Synthesis of 9-hydroxy-3-methoxy-9H-indene [1,2-b] pyrazine-2-carbonitrile (2): To a solution of 1 (150 mg, 0.646 mmol) in MeOH (6.5 mL), cooled to 0 ° C, NaBH4 (24 mg, 0.646 mmol) was added. After 30 min, water (5 ml) was added, MeOH was evaporated and the residue was extracted with CH2C12 (3x5 ml). The organic layers were dried over Na 2 SO 4, filtered and evaporated. EtOH was added and the precipitate was collected by filtration affording 2 (82 mg, 53%) as a white solid. 1E NMR (300 MHz, DMSO d6): d 7.93 (d, 1H), 7.76 (d, 1 H), 7.65 (d, 1 H), 7.58 (dd, 1 H), 6.27 (d, 1 H), 5.50 (d, 1 H), 4.17 (s, 3H). ESI + MS: calculated for d3H9N302: 239.24; found: 240.1 (MH +).

Synthesis of 3-methoxy-9-oxo-9H-indene [1,2-b] pyrazine-2-carbonitrile (3): To a suspension of 1 (1.10 g, 4.7 mmol) in MeOH (47 mL) was added sodium (110 mg) and the mixture was stirred at room temperature for 16 h. The precipitate was filtered, washed with EtOH and dried under vacuum to give 3 (1.03 g, 93%) as a yellow-green solid. X H NMR (300 MHz, DMSO d 6): d 7.92 (d, 1 H), 7.83 (m, 2 H), 7.71 (dd, 1 H), 4.25 (s, 3 H). ESI + MS: calculated for C? 3H7N302: 237.22; found: 238.0 (MH +).

Synthesis of 3-dimethylamino-9-oxo-9H-indene [1,2-b] pyrazine-2-carbonitrile (4): To a solution of 1 (53 mg, 0.228 mmol) in THF (2 ml) was added dimethylamine (2M in THF, 1.1 ml, 2.28 mmol). The mixture was stirred at room temperature for 16 hours, then the solvent was evaporated giving 4 (56 mg, 98%) as a yellow solid. X H NMR (300 MHz, DMSO d 6): d 7.85 (d, 1 H), 7.80-7.73 (m, 2 H), 7.67 (dd, 1 H), 3.47 (s, 6 H). ESI + EM: calculated for C? H? 0NO: 250.26; found: 251.1 (MHp).

Synthesis of 3- (2-methoxy-ethoxy) -9-oxo-9H-indene [1,2-b] pyrazine-2-carbonitrile (5): A suspension of 1 (59 mg, 0.254 mmol) in methoxyethanol (2.5 ml) was heated per MW (150 ° C, 30 min) in a sealed tube. The resulting solvent was filtered and the collected solid was washed with EtOH and dried under vacuum to yield 5 (50 mg, 70%) as a green solid. X H NMR (300 MHz, DMSO d 6): d 7.90 (d, 1 H), 7.83 (dd, 1 H), 7.82 (d, 1 H), 7.71 (dd, 1 H), 4.79 (m, 2H), 3.80 (m, 2H), 3.36 (s, 3H). ESI + MS: calculated for C? 5 HnN303: 281.27; found: 282.0 (MH +).

Synthesis of 3-hydroxy-9-oxo-9H-indeno [1,2-b] pyrazine-2-carbonitrile (6): A suspension of 1 (5.66 g, 24.3 mmol) in aqueous NaOH (2% w / v, 81 mL) was stirred at room temperature for 16 hours. The mixture was made acidic with 3N HCl to pH 1, the precipitate was collected by filtration, washed with water and dried under vacuum, giving 6 (4.88 g, 90%) as a light brown solid. X H NMR (300 MHz, DMSO de): d 7.89 (d, 1 H), 7.79-7.62 (m, 3H). ESI + MS: calculated for C? 2H5N302: 223.19; found: 224.0 (MH +).

Synthesis of 3-amino-9-oxo-9H-indene [1,2-b] pyrazine-2-carbonitrile (7): A mixture of 1 (201 mg, 0.86 mmol), ammonium acetate (331 mg, 4.3 mmol) and Na2SO (200 mg) in THF (2.9 ml) was stirred at 70 ° C in a sealed tube for 18 hours. The solvent was evaporated, water (5 ml) was added and the precipitate was filtered, washed with water and dried under vacuum, yielding 7 (171 mg, 90%) as a green solid. X H NMR (300 MHz, DMSO de): d 8.45 (bs, 2H), 7.78-7.63 (m, 4H). ESI + EM: calculated for C? 2HeN 0: 222.21; found: 223.1 (MH +).

Synthesis of 3- (4,4-difluoro-piperidin-1-yl) -9-oxo-9H-indene [1,2-b] -pyrazin-2-carbonitrile (8): 8 4,4-Difluoropiperidine hydrochloride (249 mg, 1.58 mmol) was dissolved in IN NaOH (5 mL) and extracted with CH2C12 (2x5 mL). The organic phase was dried over Na 2 SO 4, filtered and evaporated. The reflux was dissolved in THF (2 ml) and this solution was added to a solution of 1 (185 mg, 0.79 mmol) in THF (2 ml); The mixture was stirred at room temperature for 48 hours. The solvent was evaporated, the crude solid was washed with EtOH and dried under vacuum, giving 8 (245 mg, 95%) as yellow-brown eolide. X H NMR (300 MHz, DMSO de): d 7.89 (d, 1 H), 7.79 (dd, 1 H), 7.78 (d, 1 H), 7.69 (dd, 1 H), 4.13 (m, 4H), 2.22 (m, 4H). ESI + MS: calculated for C? 7H? 2F2N0: 326.31; found: 327.1 (MH +).

Synthesis of 3-chloro-9-oxo-9H-indeno [1,2-b] pyrazine-2-carbonitrile (9): A suspension of 6 (671 mg, 3.0 mmol) in POC-b (8.4 ml) was heated under stirring to 100 ° C for 17 h. The excess POCl3 was evaporated under reduced pressure and the crude was purified by flash chromatography on silica (CH2C12), yielding 9 (320 mg, 44%) as yellow solid. * H NMR (300 MHz, DMSO d6): d 8.02 (d, 1 H), 7.90 (m, 2H), 7.78 (dd, 1 H). ESI + MS: calculated for C? 2H4ClN30: 241.64; found: 241.9 (MH +).

Synthesis of 9- (1 ', 3'-dioxolan-2'-yl) -9H-indene [l # 2-b] pyrazin-2,3-dicarbonitrile (10): To a suspension of 1 (5.09 g, 21.9 mmol) in toluene (146 ml) ethylene glycol (2.4 ml, 43.8 mmol) and PTSA (6.25 g, 32.8 mmol) were added. The mixture refluxed in an apparatus Dean-Stark for 28 hours, then, the solvent evaporated. The crude was purified by flash chromatography on silica (CH2C12), giving 10 (3.87 g, 64%) as light yellow solid. X H NMR (300 MHz, DMSO d 6): d 8.03 (m, 1 H), 7.83-7.70 (m, 3 H), 4.47 (e, 4 H). ESI + MS: calculated for C? 5H8N402: 276.26; found: 277.3 (MH +).

Synthesis of 2-cyano-9- [hydroxyimino] -9H-indene [1, 2-b] pyrazine-3-carboxylic acid amide (11): To a solution of 1 (500 mg, 2.1 mmol) in CH 3 CN (20 ml) was added hydroxylamine (50 wt.% In water, 0.25 ml, 4.2 mmol) at 0 ° C. The mixture was stirred at this temperature for 2.5 hours, then the precipitate formed was collected by filtration and dried under vacuum, yielding 11 (355 mg, 62%) as red-brown eolide. * H NMR (300 MHz, DMSO d6): d 10.96 (e, lH), 8.11 (d, 1 H), 7.89 < dd, 1H), 7.88 (d, 1 H), 7.74 (dd, 1 H), 6.32 (bs, 2H). ESI + MS: calculated for C? 3H7N502: 265. 2. 3; found: 265. 9 (MH +).

Synthesis of 9- [hydroxyimino] -9H-indeno [1,2-b] pyrazin-2,3-dicarbonitrile (12): 12 To a suspension of 1 (150 mg, 0.646 mmol) in pyridine (10 ml) hydroxylamine hydrochloride (134 mg, 1.94 mmol) was added at 0 ° C. The molecular sieves were added and the mixture was stirred at room temperature for 16 hours. The insoluble residue was filtered, the solvent was evaporated and the crude was purified by flash chromatography on silica (petroleum distillate / EtOAc 9: 1), yielding 12 (55 mg, 35%) as a yellow solid in 9: 1 diastereoisomeric ratio. . H NMR for main product (300 MHz, DMSO d6): main product: d 14.28 (be, 1 H), 8.54 (d, 1 H), 8.22 (d, 1 H), 7.84 (dd, 1 H), 7.78 (dd, 1 H). ESI + MS: calculated for C? 3H5N50: 247.22; found: 247.9 (MH +).

General procedure A: Synthesis of alkyloxyimines 13a-d to R = Me b R = CH2-CH = CH2 c R = CH2-Ph d R = £ t To a solution of 1 (620 mg, 2.67 mmol) in pyridine (15 ml) an O-alkylhydroxylamine hydrochloride solution (8.31 mmol) in pyridine (15 ml) was added dropwise at 0 ° C.

The molecular sieves were added and the mixture was stirred at room temperature for 16 hours. The insoluble residue was filtered, the solvent was evaporated and the crude was purified by flash chromatography on silica (petroleum distillate / EtOAc 9: 1).

Synthesis of 9- (methoxyimino) -9H-indeno [1,2-b] pyrazin-2,3-dicarbonitrile (13a): Prepared according to general procedure A in 35% yield as a yellow solid in diastereoisomeric ratio 3: 1. XH NMR (300 MHz, CDC13) (mixture of syn-antidiaestereoisomers): main product: d 8.09 (dd, 1H), 7.94 (dd, 1H), 7.79-7.68 (m, 2H); 4.34 (s, 3H). Product minor: d 8.38 (m, 1H), 8.18 (m, 1H), 7.86-7.78 (m, 2H); 4.39 (s, 3H). ESI + MS: calculated for d4H7N50: 261.24; found: 262.1 (MH +). 9- (allyloxyimino) -9H-indeno [1,2- b] pyrazin-2,3-dicarbonitrile (13b). Prepared according to general procedure A in 15% yield as yellow solid in diastereoisomeric ratio 1: 1. X H NMR (300 MHz, DMSO de) (mixture of syn-antidiaestereoisomers): d 8.43 (m, 1 H), 8.22 (m, 1 H), 7.90-7.80 (m, 2H), 6.20 (m, 1H), 5.47 (m, 1H), 5.35 (m, 1H), 5.13 (ddd, 2H), and 8.12 (m, 1H), 7.96 (m, 1H), 7.80-7.69 (m, 2H), 6.14 (m, 1 H), 5.53 (m, 1H), 5.38 (m, 1H), 5.08 (ddd, 2H). ESI + MS: calculated for CieHgNsO: 287.28; found: 288.2 (MH +). 9-Benzyloxyimino-9H-indeno [1,2-b] pyrazin-2-3-dicarbonitrile (13c). Prepared according to general procedure A in 32% yield as yellow solid in diastereomeric ratio 2: 1. * H NMR (300 MHz, DMSO d6) (mixture of eyn-antidiaetereomers): d 8.42 (m, 1 H), 8.21 (m, 1 H), 7.88-7.78 (m, 2 H), 7.56-7.49 (m, 2 H) ), 7.47-7.33 (m, 3H), 5.67 (s, 2H) and 8.11 (m, 1H), 7.97 (m, 1H), 7.79- 7.69 (m, 2H), 7.56-7.49 (m, 2H), 7.47-7.33 (m, 3H), 5.63 (s, 2H). ESI + MS: calculated for C20HuN5O: 337.34; found: 338.2 (MH +). 9-Ethoxyimino-9H-indene [1,2-b] pyrazin-2,3-dicarbonitrile (13d).

Prepared according to general procedure A in 28% yield as a yellow solid in diastereomeric ratio 7: 3. X H NMR (300 MHz, DMSO d 6) (mixture of syn-antidiaestereoisomers): d 8.44 (m, 1 H), 8.22 (m, 1 H), 7.84 (m, 2 H), 4.65 (q, 2 H), 1.48 (t , 3H) and 8.12 (m, 1 H), 7.98 (m, 1H), 7.75 (m, 2H), 4.61 (q, 2H), 1.44 (t, 3H). ESI + MS: calculated for C15H9N5O: 275.27; found: 276.2 (MH +).

Synthesis of 9- [phenylimino] -9H-indeno [1,2-b] pyrazin-2,3-dicarbonitrile (14): To a suspension of 1 (118 mg, 0.51 mmol) and molecular sieves in toluene (3 ml) aniline (0.037 ml, 0.41 mmol) was added. The mixture was heated by MW (150SC, 10 min), then the solvent was evaporated and the crude was purified by flash chromatography on silica (petroleum distillate / EtOAc 9: 1), yielding 14 (93 mg, 60%) as red solid in diatherreoeomeric ratio 7: 3.

X H NMR (300 MHz, CDC13): d 8.14 (d, 1 H), 7.65 (dd, 1 H), 7.50 (dd, 2H), 7.44-7.29 (m, 3H), 7.05 (d, 2H). ESI + MS: calculated for C19H9N5: 307.32; found: 308.0 (MH +).

General procedure B: synthesis of 1,2-indandiones 15a-j - a R5 = OMe, R3 = R4 = R6 = H lü b R4 = R5 = OMe, R3 = R6 = H c R3 = Me, R4 = K5 = R6 = H d R3 - R4 = OMe, R5 = R6 = H and R5 = Me, R3 = R4 = R6 = H f R3 = R6 = OMe, R4 = R5 = H g R4 = Cl, R3 = R5 = R6 = H h R4 = F, R3 = R5 = R6 = HI R4 = OMe, R3 = R5 = R6 = H j R4 = OH, R3 = R5 = R6 = H To a substitution of 1-indanone suepeneion (5 mmol) in MeOH (12 mL) was heated to 40SC haeta, isopentyl nitrite (0.73 ml, 5.5 mmol) and 37% HCl (0.5 ml) were added.

After 1 hour at 40 SC then the formed precipitate was collected by filtration, washed with MeOH and dried under empty. The solid obtained was suspended in CH20 (36% aqueous, 1.6 ml) and 37% HCl (3.2 ml) and the mixture was stirred at room temperature for 16 hours. Water (20 ml) was added and the suepeneion extracted with CH2C12 (3x15 ml). The organic phases collected were dried over Na 2 SO 4, filtered and evaporated. The crude product was used without further purification. 6-Methoxy-indan-1, 2-dione (15a). Prepared according to general procedure B in 60% yield as a yellow solid. ESI + MS: calculated for C? 0H8O3: 176.17; found: 177.0 (MH +). ,6-Dimethoxy-indan-1, 2-dione (15b). Prepared according to general procedure B in 95% yield as light brown solid. ESI + MS: calculated for C11H10O: 206.20; found: 207.0 (MH +). 4-Methyl-indan-1, 2-dione (15c). Prepared according to general procedure B in 60% yield as a yellow solid. ESI + MS: calculated for C? 0H8O2: 160.17; found: 161.0 (MH +). 4,5-Dimethoxy-indan-1, 2-dione (15d). Prepared according to general procedure B in 94% yield as a yellow solid. ESI + MS: calculated for C? H? 0O4: 206.20; found: 207.0 (MH +). 6-Methyl-indan-l, 2-dione (15e). Prepared according to general procedure B in 61% yield as a yellow solid. ESI + EM: calculated for C? 0H8O2: 160. 17; found: 161. 0 (MH +). 4, 7-Dimethoxy-indan-1, 2-dione (15 £). Prepared according to general procedure B in 52% yield as light brown eolid. ESI + MS: calculated for C11H10O4: 206.20; found: 207.0 (MH +).

-Chloro-indan-l 2-dione (15g). Prepared according to general procedure B in 57% yield as yellow solid. ESI + MS: calculated for C9H5C102: 180.59; found: 181.0 (MH +).

-Fluoro-indan-l, 2-dione (15h). Prepared according to general procedure B in 63% yield as yellow solid. ESI + MS: calculated for C9H5F02: 164.14; found: 165.0 (MH +).

-Methoxy-indan-1, 2-dione (15i). Prepared according to general procedure B in 70% yield as yellow solid. ESI + MS: calculated for C10H8O3: 176.17; found: 177.1 (MH +).

-Hydroxy-indan-1, 2-dione (15j). Prepared according to general procedure B in 64% yield as a yellow solid. ESI + MS: calculated for C9H603: 162. fifteen; found: 163. 0 (MH +) General procedure C: pyrazine ring formation a 5 = OMe, R3 = R4 = R6 = H b R4 = R5 = OMe, R3 = R6 = H c R3 = Me, R4 = R5 = R6 = H d R3 = R4 = OMe, R5 = R6 = H and R5 = Me, R3 = R4 = R6 = H f R3 = R6 = OMe, R4 = R5 = H To a suspension of 15 (3 mmol) in iPrOH (15 ml) a diamine-maleodinitrile suepeneion (324 mg, 3 mmol) in iPrOH (15 ml) was added. The mixture was stirred at room temperature for 24 hours, then, the precipitate was collected by filtration, washed with EtOH and dried under vacuum. 6-Methoxy-9H-indene [1,2-b] pyrazin-2,3-dicarbonitrile (16a). Prepared according to general procedure C in 65% yield as solid coffee. ESI + MS: calculated for C? 4H8N40: 248.25; found: 249.0 (MH +). 6, 7-Dimethoxy-9H-indene [1,2-b] pyrazin-2,3-dicarbonitrile (16b).

Prepared according to general procedure C in 91% yield as light brown solid. ESI + MS: calculated for C? 5H10N4O2: 278. 27; Found: 279.0 (MH +). 8-Methyl-9H-indene [1,2-b] pyrazin-2,3-dicarbonitrile (16c). Prepared according to general procedure C in 60% yield as light brown solid. XH NMR (300 MHz, CDC13): d 8.03 (d, 1 H), 7.57-7.46 (m, 2H), 4.03 (e, 2H), 2.50 (s, 3H). ESI + MS: calculated for Ci 4 H 8 N: 232. 25; found: 233. 0 (MH +). 7 8-Dimethoxy-9H-indene [1,2-b] pyrazin-2,3-dicarbonitrile (16d). Prepared in accordance with general procedure C in 72% yield as a yellow solid. 1 H NMR (300 MHz, CDC13): d 7.90 (d, 1 H), 7.17 (d, 1 H), 4.10 (s, 2H); 4.02 (e, 3H), 4.01 (s, 3H). ESI + MS: calculated for C? 5H? 0N4O2: 278.27; found: 279.2 (MH +). 6-Methyl-9H-indene [1,2-b] pyrazin-2,3-dicarbonitrile (16e). Prepared according to general procedure C in 48% yield as light brown solid. ESI + EM: calculated for C? H8N: 232.25; found: 233.0 (MH +). ,8-Dimethoxy-9H-indene [1,2-b] pyrazin-2,3-dicarbonitrile (16f). Prepared according to general procedure C in 45% yield as light brown eolid. ESI + EM: calculated for C? 5H? Or N402: 278.27; found: 278.9 (MH +).

General procedure D: oxidation of methylenic group a -R5 = OMe, R3 = R4 = R6 = H b R4 = R5 = OMe, R3 = R6 = H c R3 = Me, R4 = R5 = R6 = H d R3 = f? 4 = OMe, R5 = R6 = H e R5 = Me, R3 = R4 = R6 = H f R3 = R6 = OMe, R4 = R5 = H To a suspension of 16 (0.8 mmol) in AcOH (1.6 mL) a suspension of K2Cr207 (434 mg, 1.44 mmol) in AcOH (0.8 mL) and water (0.2 mL) was added. The mixture was slowly heated to 100 ° C and stirred vigorously at this temperature for 1 hour. The hot suspension was poured into water (10 ml) and the precipitate was collected by filtration, washed with water and dried under vacuum. 6- ethoxy-9-oxo-9H-indene [1,2-b] pyrazin-2,3-dicarbonitrile (17a).

Prepared in accordance with general procedure D in 70% yield as light brown solid. 1 H NMR (300 MHz, CDC13) d 7.92 (d, 1H), 7.48 (d, 1H), 7.18 (dd, 1H), 4.04 (s, 3H). ESI + MS: calculated for C? 4H6N402: 262.23; found: 263.0 (MH +). 6,7-Dimethoxy-9-oxo-9H-indene [1,2-b] pyrazin-2,3-dicarbonitrile (17b). Prepared according to general procedure D in 37% yield as a red solid. XH R N (300 MHz, CDC13): d 7.39 (s, 1H), 7.37 (s, 1H), 4.10 (s, 3H), 4.03 (s, 3H). ESI + MS: calculated for Ci5H¿N4? 3: 292.26; found: 293.0 (MrT). 8-Methyl-9-oxo-9H-indene [1,2-b] pyrazin-2,3-dicarbonitrile (17c). Prepared according to general procedure D in 91% yield as a yellow solid. 1 H NMR (300 MHz, DMSO 368K): d 7.90 (d, 1H), 7.79 (dd, 1H), 7.61 (d, 1H); 2. "69 (s, 3H) ESI + MS: calculated for C? HeN40: 246.23, found: 247.0 (MH +). 7, 8 -Dimet oxy-9 -oxo-9H-indene [1,2-b] pyrazin-2,3 -dicarbonitrile (17d). Prepared according to general procedure D in 71% yield as a red solid. X H NMR (300 MHz, DMSO 368K): d 7.74 (d, 1H), 7.49 (bd, 1 H), 4.07 (e, 3H), 3.99 (s, 3H). ESI + EM: calculated for CisH ^ Os: 292.26; found: 293.0 (MH +). 6-ethyl-9-oxo-9H-indene [1,2-b] pyrazin-2,3-dicarbonitrile (17e).

Prepared according to general procedure D in 73% yield as a yellow solid. X H NMR (300 MHz, DMSO d 6): d 7.95 (d, 1 H), 7.86 (d, 1 H), 7.63 (dd, 1 H), 2.52 (s, 3 H). ESI + MS: calculated for C? 4H6N40: 246.23; found: 247.0 (MH +). , 8-Dimethoxy-9-oxo-9H-indene [1,2-b] pyrazin-2,3-dicarbonitrile (17f). Prepared according to general procedure D in 68% yield as solid coffee. X H NMR (300 MHz, CDC13): d 7.35 (d, 1 H), 7.24 (d, 1 H), 4.06 (s, 3 H), 4.05 (e, 3 H). ESI + MS: calculated for C? 5H8N03: 29226; found: 293.0 (MH +).

General procedure E: Formation and oxidation of pyrazine ring of a container g R4 = Cl, R3 = R5 = R6 = H h R4 = F, R3 = R5 = R6 = H i R4 = OMe, R3 = R5 = R6 = H j R4 = OH, R3 = R5 = R6 = H To a euepeneion of 15 (3 mmol) in iPrOH (15 ml) a suspension of diamino-maleodinitrile (324 mg, 3 mmol) in iPrOH (15 ml) was added. The mixture was stirred at room temperature for 24 hours then for 48 hours at 80 ° C. The precipitate was collected by filtration, washed with EtOH and dried under vacuum. 7-Clo x -9-oxo-9H-indene [l # 2-b] pyrazin-2 # 3-dicarbanitrile (17g). Prepared according to the general procedure E in 40% as a yellow solid. X H NMR (300 MHz, DMSO d 6): d 8.13 (d, 1 H), 8.04 (bs, 1H), 7.97 (bd, 1 H). ESI + MS: calculated for C 3 H 3 ClN 40: 266.65; found: 266.9 (MH +). 7-Fluoro-9-oxo-9H-indene [1,2-b] pyrazin-2,3-dicarbonitrile (17h). Prepared according to the general procedure E in 55% as roea eolid. X H NMR (300 MHz, CDC13): d 8.03 (dd, 1H), 7.74 (dd, 1H), 7.42 (ddd, lH). ESI + MS: calculated for Ci3H3FN40: 250.19; found: 251.0 (MH +). 7-Methoxy-9-oxo-9H-indeno [1,2-b] pyrazin-2,3-dicarbonitrile (17i). Prepared according to the general procedure E in 23% as light brown eolid. XH NMR (300 MHz, CDC13): d 7. 92 (d, 1 H), 7.48 (d, 1 H), 7.18 (dd, 1 H), 4.03 (s, 3H). ESI + MS: calculated for C? 4H6N402: 262.23; found: 263. 0 (MH +). 7-Hydroxy-9-oxo-9H-indeno [l 2-b] pyrazin-2,3-dicarbonitrile (17j).

Prepared according to the general procedure E in 35% as an orange solid. The product was not purified by precipitation but, after evaporation of the solvent, by flash chromatography (CH2Cl2 / MeOH 9: 1). 1 H NMR (300 MHz, DMSO d 6): d 11.66 (fe, 1 H), 7.84 (d, 1 H), 7.30 (d, 1 H), 7.09 (dd, 1 H). ESI + MS: calculated for C? 3 H 4 N 402: 248.20; found: 249.0 (MH +).

Synthesis of benzo [b] thiof en-2,3-dione (18): 18 To a benzentiol solution (1 ml, 9.7 mmol) in Et20 (30 ml) at 0 ° C of oxalyl chloride (0.94 ml, 10.7 mmol) was added dropwise. The mixture was stirred at room temperature for 1.5 hours, then, the solvent was evaporated under reduced pressure. The crude was dissolved in CH2C12 (40 ml) and a solution of A1C13 (4.75 g, 35 mmol) in CH2C12 (32 ml) was added dropwise to 0SC. The mixture was stirred for 16 h at room temperature, then ice and 1M HCl were added until a clear mixture was obtained. After 1 hour, the fas-es were separated and the aqueous layer was extracted with CH2C12 (3x30 ml). The collected organic phases were dried over Na 2 SO 4, filtered and evaporated to give 18 (1.2 g, 78%) as an orange solid which was used without further purification. ESI + MS: calculated for C8H402S: 164.18; found: 165.1 (MH +).

Synthesis of benzo [4,5] thieno [2,3-b] pyrazin-2,3-dicarbonitrile (19): 18 19 18 (300 mg, 1.83 mmol) and diaminomalenedinitrile (198 mg, 1.83 mmol) were added to boiling water (10 ml). The mixture was refluxed for 1 h, then the crude precipitate was filtered, stripped in MeOH and refluxed for 10 min. After cooling to room temperature, the solid was filtered and dried under vacuum, yielding 19 (216 mg, 50%) as a brown powder. X H NMR (300 MHz, DMSO d 6): d 8.58 (d, 1 H), 8.38 (d, 1 H), 7.94 (dd, 1 H), 7.80 (dd, 1H). ESI + MS: calculated for Ci2H4N S: 236.26; found: 237.1 (MH +).

Synthesis of 5, 10-dioxo-5, 10-dihydro-benzo [g] quinoxalin-2,3-dicarbonitrile (20): A suspension of 1, 2, 3, 4-tetraoxo-1,2,3,4-tetrahydro-naphthalene dihydrate (214 mg, 0.95 mmol) and diaminomalenedinitrile (102 mg, 0.95 mmol) in EtOH (9.5 ml) and a catalytic amount of AcOH was stirred at room temperature for 24 hours. The precipitate was collected by filtration, washed with EtOH and dried under vacuum, obtaining 20 (65 mg, 35%) as a light brown solid. X H NMR (300 MHz, DMSO d 6): d 9.16 (m, 2H), 8.24. (M, 2H).

Synthesis of 2-cyano-9-oxo-9H-indeno [l # 2-b] pyrazin-3-yl-cyanamide (21): twenty-one Under an inert atmosphere, cyanamide (44 mg, 1037 mmol) was dissolved in dry DMF (1 ml) and NaH (21 mg, 0.519 mmol) was added in one portion. After 20 min, a solution of 1 (96 mg, 0.415 mmol) in dry DMF (2 ml) was added dropwise. After lh the solvent was evaporated and the crude was purified by flash chromatography (CH2Cl2 / MeOH 8: 2) giving 21 (84 mg, 82%) as an orange solid. X H NMR (300 MHz, DMSO d 6): d 7.85 (ddd, 1 H), 7.77 (ddd, 1 H)? 7.76 (m, 1 H), 7.67 (ddd, 1H). ESI + MS: calculated for C? 3H5N50: 247.22; found: 248.1 (MH +).

Synthesis of 3- (l-cyano-2-ethoxy-2-hydroxy-vinyl) -9-oxo-9H- Ethyl cyanoacetate (110 mg, 0.970 mmol) was dissolved, under an inert atmosphere, in dry DMF (1 ml) and NaH (39 mg, 0.970 mmol) was added in one portion. After 30 min, a solution of 1 (150 mg, 0.646 mmol) in dry DMF (2 ml) was added dropwise. After 15 min MeOH was added and the solution was stirred for 10 min. The eluents were evaporated and the crude was purified by flash chromatography (EtOAc: MeOH 9: 1) to give 22 as a dark red solid (200 mg, 97%). X H NMR (300 MHz, DMSO d 6): d 7.78-7.55 (m, 4 H), 4.11 (q, 2 H), 1.22 (t, 3 H). ESI + MS: calculated for C? 7Hl0N4O3: 318.29; found: 319.2 (MH +).

Synthesis of 3-ethylsulfanyl-9-oxo-9H-indene [1,2-b] pyrazine-2-carbonitrile 23 To a mixture of ethanethiol (62 μL, 0.84 mmol) and INN NaOH (0.5 mL, 0.5 mmol) in THF (2.1 mL) 9 (101 mg, 0.42 mmol) was added.The mixture was stirred at room temperature for 30 minutes. After the solvent was evaporated under reduced pressure, the residue was dissolved in H20 (4 ml) and extracted with CH2C12 (2x4 ml) The organic phases collected were dried over Na2SO4, filtered and evaporated. flash chromatography (CH2C12) yielding 23 (98 mg, 87%) as an orange solid.1H NMR (300 MHz, CDC13): d 7.92 (d, lH), 7.86 (d, 1H), 7.73 (ddd, 1H), 7.63 (ddd, 1 H), 3.44 (q, 2H), 1.51 (t, 3H) ESI + MS: calculated for C? 4H9N30S: 267.31, found: 268.1 (MH +).

General procedure F: synthesis of alkyloxyimines To a suspension of 17g (151 mg, 0.56 mmol) in pyridine (5.6 ml) O-alkylhydroxylamine hydrochloride (1.68 mmol) and molecular sieves were added and the mixture was stirred at 60 SC for 1.5 h. The insoluble residue was filtered, the solvent was evaporated and the crude was purified by flash chromatography on silica (petroleum distillate / CH2C12 1: 1). 7 -. 7-Chloro-9-methoxy imino-9H-indene [1,2-b] pyrazin-2,3 -dicarbonitrile (24a) Prepared according to general procedure F in 65% yield as light brown solid in diastereoisomeric ratio 1 :1. XH NMR (300 MHz, CDC13) (mixture of eyn-antidiaeetereoieómeroe): d 8.36 (d, 1H), 8.04 (d, 1H), 7.64 (dd, 1 H), 4.43 (e, 3H) and 7.94 (d, 1 H), 7.89 (d, 1 H), 7.54 (dd, 1H), 4.36 (s, 3H). ESI + EM: calculated for C? H6ClN50: 295.69; found: 296.0 (MH +). 9-Allyloxyimino-7-chloro-9H-indene [1,2-b] pyrazin-2,3-dicarbonitrile (24b) Prepared according to general procedure F in 56% yield as a light brown solid in diastarreoeomeric ratio 1: 1. 1 H NMR (300 MHz, CDC13) (mixture of syn-antidiaestreoisomers): d 8.41 (d, 1 H), 8.07 (d, 1 H), 7.67 (dd, 1 H), 6.22-6.03 (m, 1 H) , 5.47 (m, 1 H), 5.36 (m, 1H), 5.15 (m, 2H) and 7.97 (d, 1 H), 7.94 (d, 1 H), 7.57 (dd, 1 H), 6.22-6.03 (m, 1H), 5.47 (m, 1 H), 5.40 (m, 1 H), 5.05 (m, 2H). ESI + MS: calculated for C? 6H8ClN50: 321.73; found: 322.1 (MH +). 6-Chloro-9-oxo-9H-indene [1,2-b] pyrazin-2,3 -dicarbonitrile (25): A mixture of 5-chloro-l-indanone (1.05 g, 6.28 mmol) and N-bromosuccinimide (2.23 g, 12.56 mmol) in DMSO (25 mL) was stirred overnight at 40 ° C and 5h at 80 ° C under vacuum. Water (125 ml) was added and the mixture was extracted with CH2C12 (25 ml). The aqueous phase was saturated with brine and solid NaCl and extracted with CH2C12 (4x80 ml). The organic phases were added over Na 2 SO 4 and the solvent was evaporated. The crude was diered in EtOH (63 ml), diamine aleonitrile (678 mg, 6.28 mmol) and a catalytic amount of AcOH were added and the mixture was stirred at 802C for 45 min. The precipitate was collected by filtration and washed with EtOH (464 mg). The filtered solution was evaporated and the crude was purified instantly.

Synthesis of 2- (2-cyano-9-oxo-9H-indeno [l, 2-b] pyrazin-3-yl) acetamide 1 26 The procedure for the preparation of starting material 1 was described in a previous experiment section.

Tert-butyl cyanoacetate (292 mg, 2.07 mmol) was dissolved, under an inert atmosphere, in dry DMF (4 ml) and NaH (-60% dispersion in mineral oil, 90 mg, 2.24 mmol) was added in portions. After 15 min, a solution of 1 (400 mg, 1.72 mmol) in py_Feco (3 ml) was added dropwise. After 16h MeOH was added, the solvents were evaporated and the crude was purified by flash chromatography (EtOAc: MeOH 9: 1) to give tert-butyl ester of cyano- (2-cyano-9 -oxo-9H-indene [ 1,2-b] pyrazin-3-yl) -acetic acid as a dark red solid. A solution of the intermediate in dioxane / H20 / TFA (5: 1: 1, 7 ml) was stirred at 50 ° C for 4 h. The precipitate was collected by filtration and crystallized from CH 3 CN, yielding 26 (172 mg, 38% over 2 steps) as a pink solid. H NMR (300 MHz, EMSO de): d 8.22 (bs, lH), 7.94 (dd, 1 H), 7.93 (bs, 1H), 7.85 (dd, 1H), 7.84 (ddd, 1H), 7.69 (ddd) , lH), 4.75 (s, 2H). ESI + MS: calculated for C? H8N402: 264.25; found: 265.1 (MHp.

General procedure 6: synthesis of O-alkyloximes 1.17g, 25 27a-c 1, a R1 = R2 = H, R3 = -CH2CH2OPr? 17g, b R1 = Cl, R2 = H, R3 = -CH2CH2OPh 25, c R1 = H, R2 = Cl, R3 = -CH2CH = CH2 A with a suspension of 1.17g, 25 (0.72 mmol) in pyridine (7 ml ) of O-alkylhydroxylamine hydrochloride (2.16 mmol) and the molecular sieves were added and the mixture was stirred at 60aC for 2h. The insoluble residue was filtered, the solvent evaporated and the crude was purified by flash chromatography (petroleum ether / CH2Cl2 1: 1). 9- (2-phenoxy-ethoxyimmo) -9H-indene [1,2-b] pyrazin-2,3-dicarbonitrile (27a). Prepared according to general procedure D in 46% yield as a yellow solid in diastereomeric ratio 1: 1. X H NMR (300 MHz, DMSO d 6) (mixture of eyn-antidiaetereomers): d 8.11 (d, 1 H), 7.98 (d, 1 H), 7.75 (m, 2 H), 7.28 (m, 2 H), 7.01 (d. m, 2H), 6.93 (m, 1H), 4.89 (m, 2H), 4.46 (m, 2H) and 8.40 (d, 1H), 8.21. { d, 1H), 7.82 (m, 2H), 7.28 (m, 2H), 7.01 (m, 2H), 6.93 (m, 1 H), 4.94 (m, 2H), 4.46 (, 2H). ESI + MS: calculated for C2? H13ClN502: 367.37; found: 368.1 (MH +). 7-Chloro-9- (2-phenoxy-ethoxyimino) -9H-indene [1,2-b] pyrazin-2,3-dicarbonitrile (27b). Prepared in accordance with general procedure D in 75% yield as yellow solid in diastereomeric ratio 6: 4. XH NMR (300 MHz, CDC13) (mixture of syn-antidiaestereoisomers): d 8.00 (d, 1H), 7.96 (d, 1 H), 7.61 (dd, 1 H), 7.27 (m, 2H), 6.95 (m , 3H), 4.94 (m, 2H), 4.45 (m, 2H) and 8.46 (d, 1 H), 8.09 (d, 1 H), 7.70 (dd, 1 H), 7.27 (m, 2H), 6.95 (m, 3H), 5.02 (m, 2H), 4.46 (m, 2H). ESI + MS: calculated for C2? H? 2 ClN502: 401.82; found: 402.0 (MH +). 9-Allyloxyimino-6-chloro-9H-indene [1,2-b] pyrazin-2,3-dicarbonitrile (27c). Prepared according to general procedure D in 87% yield as light yellow solid in diastereomeric ratio 6: 4. 1 H NMR (300 MHz, CDC13) (mixture of syn-antidiaestereoisomers): d 8.34 (d, 1H), 8.10 (d, 1 H) ', 7.65 (dd, 1 H), 6.10 (m, 1 H), 5.48 (m, 1 H), 5.34 (m, 1 H), 5.11 (m, 2H) and 8.01 (d, 1 H), 7.88 (d, 1 H), 7.58 (dd, 1 H), 6.10 (m, 1 H), 5.42 (m, 1 H), 5.33 (m, 1H), 5.03 (m, 2H). ESI + MS: calculated for C? 6H8ClN50: 321.73; found: 322.1 (MH +).

General procedure H: synthesis of substituted 1-indanones 28a-c a R1 = Me, R2 = F, R3 = H b R1 = H, R2 = R3 = Cl c R1 = R2 = H, R3 = Et -Fluoro-4-methyl-indan-l-one (28a) A benzaldehyde 3-fluoro-2-methyl (1.9 g, 14.0 mmol), malonic acid (2.2 g, 21.0 mmol) and piperidine (138 μl, 1.4 mmol) in pyridine (14 ml) was refluxed for 16 h. After cooling, 6N HCl was added up to pH = 1, then the precipitate was collected by filtration and washed with H20. The dried solid was hydrogenated at 30 psi (2,109 kg / cm 2) for 2 h using a Parr apparatus with 10% Pd / C (0.2 g) as catalyst and MeOH (140 ml) as solvent. The suspension was filtered through Celite pad and the solvent was evaporated under reduced pressure. To a solution of aryl propionic acid (2.24 g, 12.3 mmol) in CH2C12 (61 mL), oxalyl chloride (3.2 mL, 36.9 mmol) and few drops of DMF were added and the mixture was stirred for 1 h at room temperature. The solvent was evaporated and the residue was added, dissolved in CH2C12 (61 ml), to a sodium allopene of A1C13 (4.92 g, 36.9 mmol) in CH2C12 (61 ml) cooled to 0 ° C. The mixture was refluxed for 16 h and then emptied on ice. The phases were separated and the extract extracted with CH2C12 (2x50 ml). The organic faees collected were collected on Na2SO4, filtered and evaporated. The crude was purified by flash chromatography (petroleum ether / EtOAc 7: 3) to give 28a (1.85 g, 76% over 3 steps) as a white solid. * H NMR (300 MHz, CDC13): d 7.60 (dd, 1 H), 7.05 (dd, 1H), 3.03 (dd, 2H), 3.72 (dd, 2H), 2. 2 7 (d, 3 H). ES I + EM: cal cured for C? 0H9FO: 164.18; found: 165.2 (MH +). ,6-Dichloro-indan-l-one (28b) A mixture of 3,4-Dichlorophenyl propionic acid (1.95 g, 8.9 mmol) and polyphosphoric acid (19 g) was stirred at 120 ° C for 8 h. The ice was added and the mixture was extracted with CH2C12 (2x20 ml). The collected organic phases were dried over Na 2 SO 4, filtered and evaporated. The crude was purified by flash chromatography (petroleum ether / EtOAc 8: 2) to afford the 5,6-indanon disubetituido 28b eeperated (143 mg, 8%) as white solid. 1 H NMR (300 MHz, CDC13): d 7.82 (s 1 H), 7.60 (bs, 1 H), 3.11 (dd, 2H), 3.73 (dd, 2H). ESI + MS: calculated for C9H6C120: 201.05; found: 202.1 (MH +). 6-Ethyl-indan-l-one (28c). To a thick mixture of polyphosphoric acid (20 g) was heated at 60 ° C 4-ethyl-phenyl propionic acid (1.26 g, 7.1 mmol) was added in portions. The mixture was heated to 80 ° C for 2 h and then emptied on ice. Suspeneion was extracted with CH2C12 (2x10 ml), the organic phase was dried over Na2SO4, filtered and evaporated. The product (1.13 g, 99%) was used without further purification. ESI + MS: calculated for CnH? 20: 160.22; found: 161.1 (MH +).

General procedure I: synthesis of substituted 1,2-indandiones a R1 = Me, R2 = F, R3 = H c R1 = R2 = H, R3 = € t To a suspension of substituted 1-indanone (5 mmol) in MeOH (12 ml) was heated to 40 ° C, isopentyl nitrite (0.73 ml, 5.5 mmol) and 37% HCl (0.5 ml) were added. After lh at 40 ° C then the formed precipitate was collected by filtration, washed with MeOH and dried under vacuum. The solid obtained was suspended in CH20 (36% aqueous, 1.6 ml) and 37% HCl (3.2 ml) and the mixture was stirred at room temperature for 16 h. Water (20 ml) was added and the suspension was extracted with CH2C12 (3x15 ml). The organic phases collected were dried over Na 2 SO 4, filtered and evaporated. The crude product was used without further purification.

-Fluoro-4-Methyl-indan-l-2-dione (29a) Prepared according to general procedure F in 95% yield as a yellow solid. ESI + MS: calculated for C? 0H7FO2: 178.16; found: 179.2 (MH +). 6-ethyl-indan-1, 2-dione (29c) Prepared according to general procedure F in 98% yield as a yellow solid. ESI + MS: calculated for CnH? 0O2: 174.20; found: 175.1 (MH +).

Synthesis of 7-Fluoro-8-methyl-9-oxo-9H-indeno [1,2-b] pyrazin-2,3-dicarbonitrile (30): To a suepeneion of 29a (578 mg, 3.24 mmol) in MeOH (32 ml) diaminomaleodinitrile (420 mg, 3.89 mmol) and AcOH (1.6 ml) were added. The mixture was stirred at room temperature for 16 h and then the solvent was evaporated under reduced pressure. The crude was purified by flash chromatography (CH2C12) yielding 7-fluoro-8-Methyl-9H-indene [1,2-b] pyrazin-2,3-dicarbonitrile as light brown solid. To a suepeneion of the intermediate (2.94 mmol) in 95: 5 AcOH / H20 (10 ml) K2Cr207 (865 mg, 2.94 mmol) was added in portions. The mixture was stirred at 60 ° C for 4 h. The warm pellet was poured into water (50 ml) and the precipitate was collected by filtration, washed with water and dried under vacuum. The crude was purified by inantantial chromatography (CH2Cl2 / petroleum ether 7: 3) to give 30 (707 mg, 83% over 2 steps) as an orange solid. 1 H NMR (300 MHz, CDC13): d 7.86 (dd, 1 H), 7.40 (dd, 1 H), 2.62 (s, 3H). ESI + MS: calculated for C? 4H5FN40: 264.22; found: 265.1 (MH +).

Synthesis of 6,7-Dichloro-9-oxo-9H-indene [1,2-b] pyrazin-2,3-dicarbonitrile (31): A mixture of 29b (161 mg, 0.80 mmol) and N-broposuccinimide < 285 mg, 1.6 mmol) in EMSO (3.2 ml) was stirred overnight at 40 ° C and 5h at 80 ° C under vacuum. Brine (7 ml) was added and the mixture was extracted with CH2C12 (3x5 ml). The organic phases collected were dried on Na2SO4 and the solvent was evaporated. The crude was dissolved in EtOH (8 ml), diaminomaleonitrile (112 mg, 1.04 mmol) and a catalytic amount of AcOH were added and the mixture was stirred at 80 ° C for 2 h. The solvent was evaporated and the crude was purified by flash chromatography (CH2Cl2 / petroleum ether 1: 1) to provide 31 (30 mg, 13% over 2 steps) as a yellow solid. X H NMR (300 MHz, CDC13): d 8.07 (s, 1 H), 7.96 (e, 1 H). ESI + MS: calculated for C? 3H2Cl2N0: 301.09; found: 301.2 (MH +).

Synthesis of 6-ethyl-9-oxo-9H-indene [1,2-b] pyrazin-2,3-dicarbonitrile (32): A suspension of 29c (298 mg, 1.71 mmol) and diaminemaleonitrile (185 mg, 1.71 mmol) in iPrOH (17 mL) was stirred at 80 ° C for 20 h. The solvent was evaporated under reduced pressure and the crude was purified by flash chromatography (CH2C12). The product obtained was purified by preparative HPLC, obtaining 32 as a yellow solid with regioisomeric mixture 7: 3 with the 7-ethyl analogue. H. NMR (300 MHz, CDC13): Main product: d 7.95 (d, 1H), 7.80 (m, 1 H), 7.67 (bd, 1 H), 2.83 (q, 2H), 1.33 (t, 3H); minor product: d 7.89 (d, 1 H), 7.89 (m, 1H), 7.56 (bd, 1H), 2.86 (q, 2H), 1.36 (t, 3H). ESI + MS: calculated for Ci5H8 40: 260.26; found: 261.1 (MHp.

Synthesis of 2-cyano-9- [hydroxyimino] -9H-indenotl, 2-b] pyrazine-3-carboxylic acid amide (33): To a solution of 1 (4.89 g, 21.0 mmol) in CH3CN (140 ml) hydroxylamine (50 wt.% In water, 2.6 ml, 42 mmol) was added at 0 ° C. The mixture was stirred at this temperature for 2.5 h, then the formed precipitate was collected by filtration and dried under vacuum, yielding 33 (5.41 g, 97%) as light brown eolid. 1U NMR (300 MHz, DMSO d6): d 10.96 (s, 1 H), 8.11 (d, 1H), 7.89 (dd, 1 H), 7.88 (d, 1 H), 7.74 (dd, 1 H), 6.32 (bs, 2H). ESI + MS: calculated for C? 3H7N502: 265.23; found: 265.9 (MH +).

General procedure J: Synthesis of 9-alkyloxyimino-9H-indene [1,2-b] pyrazine-3-carboxylic acid amide A suepeneium of 33 (610 mg, 2.3 mmol), Cs2C03 (1.5g, 4.6 mmol), Kl (1.14 g, 6.9 mmol) and alkyl bromide (6.9 mmol) in DMF (12 mL) was stirred at 50 ° C for the night. The solvent was evaporated under reduced pressure and the crude was purified by flash chromatography (CH2Cl2 / MeOH 95: 5). 9-Allyloxyimino-2-cyano-9H-indene [1,2-b] pyrazine-3-carboxylic acid amide (34a). Prepared according to the general procedure -G in 35% yield as an orange solid in 55:45 diastereomeric ratio. X H NMR (300 MHz, DMSO de): d 8.68 (bs, 2H), 8.00 (d, 1 H), 7.90-7.78 (m, 2H), 7.65 (dd, 1 H), 6.16-6.01 (m, 1 H), 5.42 (m, 1 H), 5.28 (m, 1 H), 4.78 (ddd, 2H) and 8.56 (bs, 2H), 7.90-7.78 (m, 3H), 7.66 (dd, 1 H), 6.16-6.01 (m, 1 H), 5.36 (m, 1 H), 5.24 (m, 1 H), 4.75 (ddd, 2H). ES1 + MS: calculated for CjiHuNsOfe: 305.30; found: 306.1 (MH *). 2-Cyano-9-ethoxyimino-9H-indene [1,2-b] pyrazine-3-carboxylic acid amide (34b). Prepared according to general procedure G in 28% yield as yellow solid in diastereoisomeric ratio 6: 4. 1 H NMR (300 MHz, CDC13): d 8.05 (d, 1 H), 7.77 (d, 1 H), 7.67 (m, 1 H), 7.52 < m, 1 H), 4.48 (q, 2H), 1.42 (t, 3H) and 7.87 (d, 1 H), 7.77 (d, 1 H), 7.67 (m, 1 H), 7.52 (m, 1 H) ), 4.42 (q, 2H), 1.39 (t, 3H). ESI + MS: calculated for C15H11N5O2: 293.29; found: 294.1 (MH +). 2-Cyano-9- (2-methoxy-ethoxyimino) -9H-indene [1,2-b] pyrazine-3-carboxylic acid amide (34c) Prepared according to general procedure G in 48% yield as a solid light coffee in diastereoisomeric ratio 6: 4. H NMR (300 MHz, DMSO d6): d 8.63 (bs, 2H), 7.89-7.77 (m, 3H), 7.65 (dd, 1 H), 4.36 (m, 2H), 3.67 (m, 2H ), 3.31 (s, 3H) and 7.99 (bs, 2H), 7.89-7.77 (m, 3H), 7.65 (dd, 1 H), 4.33 (m, 2H), 3.67 < m, 2H), 3.30 (s, 3H). ESI + MS: calculated for C? 6H? 3N503: 323.31; found: 324.1 (MH +). 2-Cyano-9-methoxyimino-9H-indene [1,2-b] pyrazine-3-carboxylic acid amide (34d) Prepared according to general procedure G (the reaction mixture was stirred 48h at room temperature) in 25% yield as an orange solid in diastereoisomeric ratio 6: 4. X H NMR (300 MHz, DMSO d 6): d 8.10 (m, 1 H), 7.89 (m, 2 H), 7.74 (m, 1 H), 6.61 (bs, 2 H), 3.93 (s, 3 H) and 8.01 (m). d, 1H), 7.89 (m, 2H), 7.74 (m, 1 H), 6.37 (bs, 2H), 3.89 (s, 3H). ESI + MS: calculated for C? 4H9N502: 279.26; found: 280.1 (MH +).

Synthesis of 2-cyano-9-acetoxyimino-9H-indene [1,2-b] pyrazine-3-carboxylic acid amide (35): To a solution of 33 (1.0 g, 3.77 mmol) in dry pyridine (30 ml) cooled to 0 ° C, acetyl chloride (0.8 ml, 11.3 mmol) was added dropwise and the mixture was stirred 16 h at room temperature. Water (40 ml) was added and the precipitate was collected by filtration. The crude oil was purified by flash chromatography (CH2Cl2 / acetone / MeOH 8: 2: 0.5) and triturated with Et20 / CH2Cl2 / MeOH, giving 35 (251 mg, 21%) as a yellow solid as a single isomer. X H NMR (300 MHz, DMSO d 6): d 8.12 (d, 1 H), 7.91 (m, 2 H), 7.77 (ddd, 1 H), 7.43 (bs, 2 H), 2.27 (s, 3 H). ESI + MS: calculated for C? 5H9N503: 307.27; found: 308.1 (MH +).

Synthesis of 2-cyano-9-oxo-9H-indene [1,2-b] pyrazine-3-carboxylic acid amide (36): An euspension of 33 (522 mg, 1.97 mmol) and [bis (trifluoroacetoxy) iodo] benzene (1.69 g, 3.9 mmol) in CH3CN / H20 (9: 1, 20 mL) was stirred 24 h at room temperature. The solid was collected by filtration and washed with CH3CN. The residue was dissolved in DMSO (2 ml) and precipitated by the addition of H20. The solid obtained was filtered and dried under vacuum, yielding 36 (286 mg, 58%) as a light brown solid. X H NMR (300 MHz, DMSO d 6): d 8.65 (bs, 1 H), 8.31 (bs, lH)? 8.09 (dd, 1H), 7.93 (m, 2H), 7.77 (ddd, 1H). ESI + MS: calculated for d3H6N402: 250.22; found: 251.1 (MH +).

Synthesis of (3-carbamoyl-2-cyano-indene [1, 2-b] irazin-9-ylidenaminooxy) -acetic acid ethyl ester (37): To a suspension of 33 (300 mg, 1.1 mmol) and CS2C03 (405 mg, 1.2 mmol) in DMF (15 mL), ethyl bromoacetate (0.14 mL, 1.26 mmol) was added dropwise and the mixture was stirred at 70 ° C for 24h. The suspension was cooled to room temperature, H20 (30 ml) was added and the mixture was extracted with CH2C12 (70 ml). The organic phase was dried over Na 2 SO 4 and the volatile solvent was evaporated under reduced pressure. A 1: 1 mixture of n-hexane / iPr20 was added and after 2h the solid obtained was collected by filtration. The crude was purified by inantaneous chromatography (CH2Cl2 / MeOH 85:15) giving the 37 (85 mg, 22%) as green-brown solid. X H NMR (300 MHz, DMSO d 6): d 8.78 (bs, 1H), 8.73 (bs, 1 H), 8.00 (dd, 1 H), 7.82 (m, 2H), 7.67 (ddd, 1 H), 4.87 (s, 2H), 4.19 (q, 2H), 1.25 (t, 3H). ESI + EM: calculated for C? 7H? 3N504: 351.32; found: 352.1 (MH +).

Synthesis of (3-carbamoyl-2-cyano-indene [1,2-b] pyrazin-9-ylidene inooxy) -acetic acid (38): To a solution of 37 (70 mg, 0.2 mmol) in THF / -H20 (1: 1, 15 mL) LiOH H20 (41 mg, 1.0 mmol) was added and the mixture was stirred at room temperature. After 2h 2N HCl was added up to pH = 5. The solvent was removed under reduced pressure and the crude was purified by flash chromatography (CH2Cl2 / MeOH / AcOH 90: 10: 1) to provide 38 (41 mg, 63%) as a yellow solid. ESI + MS: calculated for C? 5H9N504: 323.27; found: 324.3 (MH +).

Synthesis of (2-bromo-acetylamino) -acetic acid ethyl ester (39): H2N '' COOEt. 39 To a mixture of glycine ethyl ester chlorohydrate - (2.0 g, 14.3 mmol) and K2CQ3 (2.1 g, 15.2 mmol) in CH2C12 (35 mL) cooled to 0-5 ° C brsmoacetyl bromide (1.36 mL, 15.6 mmol) was added dropwise. The suspension was stirred at room temperature and after 3 h the H20 (20 ml) was added. The phases were separated and the organic was washed with a saturated solution of NaHCOj (20 ml) and H ^ (20 ml) and dried over Na2SO4. The solvent was evaporated to obtain 39 as a white solid (1.2 g, 40%). ESr? : calculated for CeHioBrNC: 224.06; found: 224.0 and 226.0 (MH).

Synthesis of [2- (3-carbamoyl-2-cyano-indene [l, 2-b] pyrazin-9-ylidenaminooxy) -acetylamino] -acetic acid ethyl ester To a suspension of 33 (212 mg, 0.80), Cs2C03 (260 mg, 0.80) in DMF (15 ml), 39 (200 mg, 0.89 mmol) was added in portions and the mixture was stirred at room temperature for 2 days. H20 (30 mL) was added and the suspension was extracted with CH2C12 (70 mL). The organic phase was dried over Na 2 SO 4 and the solvent was evaporated under reduced pressure. The crude was purified by flash chromatography (CH2Cl2 / MeOH 9: 1) to give 40 (56 mg, 17%) as a yellow-brown solid. X H NMR (300 MHz, DMSO d 6): d 8.78 (m, 2 H), 8.12 (bs, 1 H), 8.05-7.78 (m, 3 H), 7.67 (m, 1 H), 4.72 and 4.69 (s, 2 H) ), 4.10 (q, 2H), 3.92 and 3.90 (s, 2H), 1.19 (t, 3H). ESI + MS: calculated for C? 9Hi6N605: 408.38; found: 409.1 (MH +).

Synthesis of [2- (3-carbamoyl-2-cyano-indene [1, 2-b] pyrazin-9-ylidenaminooxy) -acetylamino] -acetic acid (41): To a solution of 40 (60 mg, 0.15 mmol) in THF / H20 (1: 1, ml) LiOH H20 (30 mg, 0.71 mmol) was added. The mixture was stirred at room temperature and after 2h the 2N HCl was added rising to pH = 5. The solvent was removed under reduced pressure and a 1: 1 mixture of CH2Cl2 / MeOH (10 mL) was added. The solution was cooled to 0 ° C and the precipitate was collected by filtration, affording 41 (40 mg, 70%) as a green solid. H NMR (300 MHz, DMSO d6 + TFA): d 8.35 (t, 1 H), 8.13 (dd, 1 H), 7.91 (m, 2H), 7.78 (ddd, 1 H), 4.92 (s, 2H) 3.87 (d, 2H). ESI + MS: calculated for C? 7H? 2N605: 380.32; found: 381.4 (MH +).

Synthesis of 7-Chloro-3-hydroxy-9-oxo-9H-indene [1,2-b] pyrazine-2-carbonitrile (42) To a suspension of 50mg (0.19mmol) 17g and 2.2mg (5Mol-%) Na2Mo0 in 2 ml of DMSO, 82μl (0.95mmol) of an aqueous H202 solution (35%) was added dropwise. The color changed to red, and the mixture was stirred for 48 h at room temperature. After the addition of 20 mL of dichloromethane, the resulting solution was washed with water and saturated brine (3x5ml). After drying, filtration and evaporation, the crude product was purified by chromatography (DCM / MeOH 8/2) to provide 35 mg (70%) of the compound 42 as a yellow-orange powder. 1 H-NMR (d 6 -DMSO, 300 MHz): d (ppm) = 7.55 (s, 1 H); 7.64 (m, 2H). ESI'EM: calculated for C12HC1N302: 257.64; found: 255.9 (M-H +).

Synthesis of 9- [(aminocarbonyl) hydrazono] -7-chloro-9H-indene [1,2-b] pyrazin-2,3 -dicarbonitrile (43) A mixture of 600 mg (2.25 mmol) 17 g and 329 mg (2.92 mmol) eemicarbazide hydrochloride in 20 ml of acetonitrile was heated for 14 h under reflux. After such time, the CCD indicates the complete conversion of the starting product. After evaporation of the solvent, the crude product was recrystallized from aqueous ethanol, and compound 43 was obtained in slightly green crietalee (90%). 1 H-NMR (d 6 -DMSO, 400MHz): d (ppm) = 7.40 (yes, 1 H); 7.70 (yes, 1H); 7.71 (d, J = 8 Hz, 1H); 8.17 (d, J = 8 Hz, 1 H); 8.89 (s, 1 H); 10.95 (S, 1 H). ESI + MS: calculated for C? 4H6ClN70: 323.70; found: 324 (MH +).

Representative Cysteines Proteases USP5 Activity Assay USP5 was diluted in USP buffer solution (50 mM Tris HCl, 0.5 mM EDTA, 5 mM DTT, 0.01% Triton X-100, Bovine Serum Albumin 0.05 mg.ml "1 pH7. 6) Compound reserve solutions (100 mM) were stored at -20 ° C in DMSO Compounds were tested at the following final concentrations: 100 μM, 33.3 μM, 11.1 μM, 3.7 μM, 1.23 μM, 412 nM. 137 nM, 45.7 nM, 15.2 nM, 5 nM The reactions were performed as duplicates in 96-well Black LJL plates (HE microplates, Molecular Devices, final reaction volume 20 μl.) The substrate concentration for USP5 was 400 nM. Ub-AMC (Boston Biochem) The concentrations of the enzyme (USP5) in specificity assays were 300 pM The concentrations were determined in order to perform specificity tests on initial velocities at a fixed substrate concentration.The compounds were previously incubated with enzymes for 30 minutes to 2 5 ° C. The reactions were initiated by the addition of substrate to the plates containing the enzymes (+/- compounds) diluted in assay buffer. The reactions were incubated for 60 minutes at 37 ° C. The reactions were stopped by adding acetic acid (100 mM final). The readings were made in a Pherastar fluorescent reader (BMG). ? Emission 380 n; ? Excitation = 460 nm.

Data (mean values +/- standard deviation) were analyzed as control% (without compound) and grouped as a percentage against the Log of compound concentration using GraphPad (Prism). The data were adjusted to a sigmoidal model (variable slope).

Cloning and purification of USP7 USP7 encoding the ee cD was obtained by PCR amplification from placental mRNA. The USP7 cDNA was subcloned by PCR into a baculovirus expression vector (pFastBac-HT; Invitrogen). The cDNA encoding a mutated USP7 was generated by mutagenic PCR. The corresponding protein encodes a cysteine for alanine substitution in the reud 223. The sequences were checked by sequence processing of the complete open reading frame. The USP7 encoding bacmids were generated after the DHIObac transposition. The corresponding bacmids were tranefected into insect cells (Sf9). The viruses were recovered from the culture supernatant and amplified twice. The insect cells (Sf9 or High Five; Invitrogen) were infected for 72 hours. The total cell lysates were harvested and lysed in a buffer solution of lysis (50 mM Tris HCl pH7.6, 0.75% NP40, 500 mM NaCl, 10% glycerol, 1 mM DTT, 10 mM imidazole, Proteaea Inhibitor Cocktail, 20 μg AEBSF .ml "1; Aprotinin 10 μg.ml" 1). Lae proteins were purified by affinity in metal affinity resins (Metal Heel affinity resin; BD Biosciences). The binding materials were extemporaneously washed in wash buffer (50mM sodium phosphate pH7.0, 300mM NaCl, 10mM imidazole, 0.5% Triton X-100, 10% glycerol) and eluted from the resin in a buffer solution. Wash containing 250 mM imidazole. Proteins were dialysed in dialysis buffer (HCl Tris pH 7.6 20 mM, NaCl 200 mM, DTT 1 mM, EDTA 1 mM, 10% Glycerol). Protein purifications were analyzed in 4-12% NuPAGE (Invitrogen).

USP7 Activity Assay USP7 was diluted in USP buffer solution (50 mM Tris HCl, 0.5 mM EDTA, 5 mM DTT, 0.01% Triton X-100, Bovine Serum Albumin 0.05 mg.ml "1 pH7.6). Reserve solutions of compounds (100 mM) were stored at -20 ° C in DMSO Compounds were tested at the following final concentrations: 100 μM, 33.3 μM, 11.1 μM, 3.7 μM, 1.23 μM, 412 nM, 137 nM; 45.7 nM; 15.2 nM; 5 nM The reactions were performed as duplicates in 96-well Black LJL plates (HE microplates, Molecular Devices, final reaction volume 20 μl.) The substrate concentration for USP7 was 400 nM Ub-AMC ( Chem. Biol., 2003, 10, pp. 837-846) (Boston Biochem) The concentrations of the enzyme (USP7) in specificity assays was 152 pM.

The concentrations were determined in order to perform specific low-speed assays at a fixed substrate concentration. The compounds were previously incubated with enzymes for 30 minutes at 25 ° C. Reactions were initiated by the addition of eubstrate to the plates containing the enzyme (+/- compounds) diluted in assay buffer. The reactions were incubated for 60 minutes at 37 ° C. The reactions were stopped by adding acetic acid (100 mM final). The readings were made in a Pherastar fluorescent reader (BMG). ? Emieion 380 nm; ? Excitation = 460 nm. Datoe (value means +/- standard deviation) were analyzed as% control (compound ein) and grouped as a percentage against the Log of compound concentration using GraphPad (Prism). The data was adjusted to an eigmoidal model (variable slope).

USP8 Cloning and Purification USP8 encoding cDNA was obtained by PCR amplification from placental mRNA. The USP8 cDNA was subcloned by PCR into a baculovirus expression vector (pFastBac-HT; Invitrogen). The cDNA encoding a mutated USP9 was generated by mutagenic PCR. The corresponding protein encodes a cysteine for substitution of alanine at residue 786. Sequences were checked by sequence processing of the complete open reading frame. The USP7 encoding bacmidoe were generated after the DHIObac transposition. The corresponding bacmidoe were transfected into the ineecto cells (Sf9). The viruses were recovered from the culture supernatant and amplified twice. The insect cells (Sf9 or High Five; Invitrogen) were infected for 72 hours. The total cell lines were harvested and lysed in lisie buffer (50 mM Tris HCl pH7.6, 0.75% NP40, 500 mM NaCl, 10% glycerol, 1 mM DTT, 10 mM imidazole, Proteasea Inhibitor Cocktail, 20 μg AEBSF .ml "1; Aprotinin 10 μg.ml" 1). The proteins were purified by affinity in metal affinity resins (Talon Metal affinity resin, BD Biosciencee). The binding materials were washed extensively in wash buffer (50 mM eodium phosphate pH 7.0, 300 mM NaCl, 10 mM imidazole, 0.5% Triton X-100; 10% glycerol) and eluted from the resin in washing buffer containing 250 mM imidazole. Protein ee dialyzed in dialysis buffer (HCl Trie pH 7.6 20 mM, 200 mM NaCl, 1 mM DTT, 1 mM EDTA, 10% Glycerol). Lae protein purifications were analyzed in 4-12% NuPAGE (Invitrogen).

USP8 Activity Assay USP8 was diluted in USP buffer solution (50 mM Tris HCl, 0.5 M EDTA, 5 mM DTT, 0.01% Triton X-100; Bovine Serum Albumin 0.05 mg.ml "1 p-H8.8.) Compound stock solutions (100 mM) were stored at -20 ° C in DMSO.The compounds were tested at the following final concentrations: 100 μM. 33.3 μM, 11.1 μM, 3.7 μM, 1.23 μM, 412 nM, 137 nM, 45.7 nM, 15.2 nM, 5 n The reactions were performed as duplicates on 96-well Black LJL plates (HE microplates, Molecular Devices; final reaction 20 μl.) The concentration of substrate for USP8 was 400 nM Ub-AMC (Boston Biochem) The concentrations of the enzyme (USP8) in specificity assays was 630 pM The concentrations were determined in order to perform specificity tests under initial velocities at a fixed substrate concentration The compounds were previously incubated with enzymes for 30 minutes at 25 ° C. The reactions were initiated by the addition of a subeptide to the plates containing the enzymes (+/- compounds) diluted in solution trial buffer. is incubated for 60 minutes at 3.7 ° C. The reactions were stopped by adding acetic acid (100 mM final). The readings were made in a Pherastar fluorescent reader (BMG). ? Emission 380 nm; ? Excitation = 460 nm. Data (mean values +/- standard deviation) were analyzed as control% (ein compoteto) and grouped as a percentage against the Log of compound concentration using GraphPad (Prism). The data were adjusted to a sigmoidal model (variable slope).

UCH-L3 activity assay The Uch-L3 ee was diluted in USP buffer solution (50 mM Tris HCl, 0.5 mM EDTA, 5 mM DTT, 0.01% Triton X-100, Bovine Serum Albumin 0.05 mg.ml "1 pH7. 6) The reserve values of compueetoe (100mM) were stored at -20 ° C in DMSO, which were tested at the following final concentrations: 100 μM, 33.3 μM, 11.1 μM, 3.7 μM, 1.23 μM, 412 nM. 137 nM, 45.7 nM, 15.2 nM, 5 nM The reactions were performed as duplicates in 96-well Black LJL plates (HE microplates, Molecular Devices, final reaction volume 20 μl.) The substrate concentration for Uch-L3 was 400 nM Ub-AMC (Boston Biochem) The concentration of the enzyme (Uch-L3) in specificity assays was 13 pM The concentrations were determined in order to perform specificity assay under initial velocities at a fixed substrate concentration. The compounds were previously incubated with Enzyme for 30 minutes at 25 ° C. The reactions were initiated by or the addition of substrate to the plates containing the enzymes (+/- compounds) diluted in assay buffer. The reactions were incubated for 60 minutes at 37 ° C. The reactions were stopped by adding acetic acid (100 mM final). Lae readings were performed on a fluorescent Pherastar reader (BMG). d Emission 380 nm; d Excitation = 460 nm. Data (mean values +/- standard deviation) were analyzed as control% (without compound) and grouped as a percentage against the Log of compound concentration ueando -GraphPad (Priem). Loe datoe ee ajuetaron to an eigmoidal model (variable slope).

Caspase 3 activity assay Ca caepaea 3 ee diluted in Caepaea 3 buffer (100 mM Hepee pH 7.5, 10% sucrose, 0.1% CHAPS). The temperature reagent solutions (100 mM) were stored at -20 ° C in DMSO. The compounds were tested at the following final concentrations: 100 μM; 33.3 μM; 11.1 μM; 3.7 μM; 1.23 μM; 412 nM; 137 nM; 45.7 nM; 15.2 nM; 5 nM. The reactions were performed as duplicates in 96-well Black LJL plates (HE microplates, Molecular Devicee, final reaction volume 20 μl). The substrate concentration for caspase 3 specificity assay was 500 nM (Ac-DEVD-AMC, Promega). The concentration of the enzyme (Caspase 3) in specificity assays was 3.2 nM. The concentrations were determined in order to perform specificity tests under initial velocities at a fixed substrate concentration. The compounds were previously incubated with enzymes for 30 minutes at 25 ° C. The reactions were initiated by the addition of subetrato to the plates containing the enzymes (+/- compueetos) diluted in assay buffer.

Reactions were incubated for 60 minutes at 37 ° C. The reactions were stopped by adding acetic acid (100 mM final). The readings were made in a fluorescent reader Pherastar (BMG). d Emission 380 nm; d Excitation = 460 nm.

Data (mean values +/- standard deviation) were analyzed as control% (without compound) and grouped as a percentage against the Log of compound concentration using -GraphPad (Prism). The data was adjusted to a sigmoidal model (variable slope).

Cathepsin B activity assay Cathepsin B was diluted in Catepsin B buffer (20 mM Tris pH 6.8, 1 mM EDTA, 1 mM DTT). The reagent solutions of compounds (100 mM) were stored at -20 ° C in DMSO. The compounds were tested at the following final concentrations: 100 μM; 33.3 μM; 11.1 μM; 3.7 μM; 1.23 μM; 412 nM; 137 nM; 45.7 nM; 15.2 nM; 5 nM. The reactions were performed as duplicates in 96-well Black LJL plates (microplacae HE; Molecular Devicee; final reaction volume μl). The substrate concentration for cathepsin B specificity assay was 36 μM (z-RR-AMC, Calbiochem).

The concentration of the enzyme (Cathepsin B) in assays of specificity was 3.6 nM. The concentrations were determined with object of performing specificity tests at initial speeds at a fixed substrate concentration. The compounds were previously incubated with enzymes for 30 minutes at 25 ° C. The reactions were initiated by the addition of substrate to the plates containing the enzymes (+/- compueetoe) diluted in assay buffer. The reactions were incubated for 60 minutes at 37 ° C. The reactions were stopped by adding acetic acid (100 mM final). The readings were made in a Pherastar fluorescent reader (BMG). d Emission 380 nm; d Excitation = 460 nm. Data (mean values +/- standard deviation) were analyzed as% control (without compound) and grouped as a percentage against the Log of compound concentration using GraphPad (Prism). The data were adjusted to a sigmoidal model (variable slope).

Viability and cell proliferation methods HCT116 cell proliferation and viability assay HCT116 colon cancer cells were obtained from ATCC (American Type Culture Collection), and maintained in Me Coy 5A medium containing 10% FBS, 3 mM glutamine and 1% penicillin / streptomycin. The cells were incubated at 37 ° C in a humidified atmosphere containing 5% C02. Cell viability was evaluated using the MTS technique in 96-well culture plate (CellTiter 96® aqueous non-radioactive cell proliferation assay, Promega) according to the manufacturer's instructions. MTS (3- (4,5-dimethylthiazol-2-yl) -5- (3-carboxymethoxyphenyl) -2- (4-sulfophenyl) -2H-tetrazolium) is a tetrazolium derivative of MTT that is reduced in metabolically active cells in formazan that remains in the cell, eoluble. The amount of formazan, detected by its absorbance at 492 nm, is proportional to the number of metabolically active, living cells. 103 HCT116 cells were seeded per well. 24 hours later, the medium was changed and the cells were treated in triplicate with the following concentrations of each compound: 10 μM - 3.33 μM -1.11 μM - 370 nM - 123 nM - 41 nM - 14 nM and 5 nM. The compounds were diluted in 100% DMSO, whose final concentration in the cells was maintained at 0.5%. The cells were incubated with the compounds for 72 hours, and their viability is then evaluated by the addition of MTS for 2 hours. The absorbance at 492 nm was measured directly from the 96-well culture plates. Concentrations of GI50 (growth inhibition 50) of each compote were calculated using a sigmoidal variable slope configuration (Prism 4.0, Graphpad Softwares). The values represent an average of 3 independent experiments.

Feasibility and proliferation assay of PC3 cells PC-3 prostate cancer cells were obtained from ATCC, and are maintained in F-12K medium containing 7% FBS and 1% penicillin / streptomycin. The cells were incubated at 37 ° C in a humidified atmosphere containing C025%. Cell viability was evaluated using the MTS technique in 96-well culture plates (CellTiter 96® aqueous non-radioactive cell proliferation assay, Promega) according to the manufacturer's instructions. -MIS (3- (4,5-dimethyl-thiazol-2-yl) -5- (3-carboxymethoxyphenyl) -2- (4-sulfophenyl) -2H-tetrazolium) is a tetrazolium derivative of MTT which is reduced in Metabolically active cells in formazan that remains in the cell, soluble. The amount of formazan, detected by its absorbance at 492 nm, is proportional to the number of metabolically active, living cells. 2 x 103 PC3 cells were seeded per well. 24 hours later, the medium was changed and the cells were treated in triplicate with the following concentrations of each compound: lOμM - 3.33μM - 1.11μM -370nM - 123nM - 41nM - 14 nM and 5 nM. The csrppuestoe were diluted in 100% EMSO, whose final concentration in the cells was maintained at 0.5%. The cells were incubated with the compounds for 72 hours, and their viability is then evaluated by the addition of MTS for 2 hours. The absorbance at 492 nm was measured directly from the 96-well culture plates. Concentrations of GI50 (inhibition of growth 50) of each compound were calculated using a sigmoidal slope configuration (Prism 4.0, Graphpad Soft aree). The values represent an average of 3 independent experiments.

Results 1. Inhibition of activities of cysteine proteaea * ÜSPS AF: Autofluorescents AF: Autofluoreecentee UCH-3 AF: Autofluorescent Caspasa 3 AF: Autofluorescent and Cathepsin B AF: Autofluorescent nhibition of cellular availability and proliferation It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims

CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. A compound of the formula (I): (l) characterized by: m ee 0, 1 or 2, where when m = 0, (X (R2) m <) m - none ee so that it forms an open ring or an energetic link; n ee 0, 1 or 2, where when n = 0, (Y (R7) n ') n ee none so that it forms an open ring or an energetic bond; m 'and n' eon independently 0, 1 or 2; X ee a carbon atom or S or N; And it is a carbon atom, or S or N; with the proviso that m and n are not simultaneously 0; it is either a single or double link, as correeponda; ee is now none or a single link, as appropriate; Rl is selected from the group consisting of H, CN, Hal, OAlq, OH, NRCN, C (CN) = C (OH) (OAlq), SR, NRRY (Alq) nC (O) NRR Heterocycle, Aryl, Heteroaryl, wherein Alk, Aryl, Heteroaryl, heterocycle are optionally substituted by Hal, NRRY CN, OH, CF3, Aryl, Heteroaryl, OAlq, where p is 0 or 1; R3, R4, R5, R6 are each identical or different and are independently chosen from the group that connects H, OAlq, Alk, Hal, NRRY CN, OH, CF3, Aryl, Heteroaryl; R2 is chosen from the group that you have of H, 0, OH, N-OH, N-Aryl, N-OAlq, NO-Aryl, NO-Alk-Aryl, N-NR-CONRRY NO-CO-Alq, or 2 R2 linked to the same X forms together with the X a heterocycle; wherein the Alk, Aryl or heterocycle are optionally substituted by OAlk, Alk, Hal, NRRYCN, OH, CF3, OAryl, -CO- (NR-Alk-CO) p.-OAlq, -CO (NR-Alk-CO p-OH, where p 'is 0 or 1; R7 is selected from the group consisting of H, O, OH, N-OH, N-Aryl, N-OAlq, N-O-Aryl, NO-Alk-Aryl, N-NR-CONRRY NO-CO-Alk, or 2 R7 linked to the same Y forms together with the Y a heterocycle; wherein the Alkyl, Aryl or heterocycle are optionally substituted by OAlq, Alk, Hal, NRRY CN, OH, CF3, OAryl, -CO- (NR-Alk-COV-OAlq, -CO (NR-Alq-CO) p- -OH, where p 'is 0 or 1, R and R' are each identical or different and are independently chosen as the connecting group of H, Alk, wherein Alk is optionally substituted Hal, NRRY CN, OH, CF3, Aryl, Heteroaryl, or its pharmaceutically acceptable salts, hydrates or hydrated salts, or the polymorphic crystalline structures of these compounds or their optical isomers, racemates, diastereomers or enantiomers, with the exception of compounds where: R3, R4, R5, R6 = H, RI = CN, (X (R2) m,) m represents a single bond, and (Y (R7) n.) N represents -C (= N- (2-, 4-, 6-trimethylphenyl)) -, -C (= N- (2-, 6-dimethylphenyl)) -, -C (= N- (2-, 6-diethylphenyl)) -, -C (= N- (2-methylphenyl)) -, -C (= N- (2-ethylphenyl)) -, -C (= N- (2-trifluoromethylphenyl)) -, -C (= N- (2-ieopropyl-phenyl)) -, -C (= N-phenyl) -, -C (= N- (naphthyl) - or C (= 0) -, -CH2-, or R3 , R5, R6 = H, R4 = 0Me, Rl = CN, (X (R2) m.) M represents a single bond, and (Y (R7) n ') n represents -C (= 0) -, or R3 , R4, R5, R6 = H, R1 = NH2, (X (R2) m ') m- represents a single bond, and (Y (R7) n') n represents -CH2- or -CH2- CH2-; or R3, R4, R5, R6 = H, R1 = NH2, (X (R2) m.) m represents -CH2- or -CH2-CH2- and (Y (R7) n ') n represents a single bond.
2. The compound according to claim 1, characterized in that with the additional exception of the following compound: R3, R4, R5, R6 = H, R1 = CN, (X (R2) m.) M represents an energetic bond, and (Y (R7) n-) n represents -C (= N-OH) -.
3. The compound according to claim 1 or 2, characterized in that: Rl is selected from the group consisting of H, CN, Hal, OAlq, OH, NRCN, C (CN) = C (OH) (OAlq), NRRY (Alk) ) pC (O) NRR ', Heterocycle, where Alk is optionally substituted OAlq and where the heterocycle is optionally substitued by Hal where p is 0 or 1; R3, R4, R5, R6 are each identical or different and are independently selected from the group consisting of H, OAlq, Alk, Hal; - (Y (R7) n ') n-- is a single bond or Y represents a carbon atom or an S atom; R2 is chosen from the group that connects H, O; R7 is selected from the group consisting of H, O, OH, N-OH, N-OAlq, N-Aryl, NO-Aryl, NO-Alk-Aryl, NO-AlkOAryl, NO-Alk-CO (NR-Alkyl) CO) p '-OAIk, NO-Alk-CO (NR-Alq-CO) p' -OH, -N-NR-CONRRY N-CO-Alk, or 2 R7 linked to it and form together with the Y a heterocycle where p 'is 0 or 1; R and R 'are each identical or different and are independently chosen from the group that you connected from H, Alq;
4. The compound according to any of the preceding claims, characterized in that (X (R2) m ') m-- represents a single bond, n is 1, n' is 1, and e is a carbon atom.
5. The compound according to any of the preceding claims, characterized in that Rl is selected from the group consisting of H, CN, Hal, OAlq, OH, NRCN, C (CN) = C (OH) (OAlq), SR, NRRY C (0) NRR ', Heterocycle, where Alk is optionally substituted by OAlq and where the Heterocycle is optionally sub-substituted by Hal; 6.
The composition according to any of the preceding claims, characterized in that R3, R4, R5, R6 are each identical or different and are independently selected from the group consisting of H, OAlq, Alk, Hal.
The compound according to any of the preceding claims, characterized in that R7 is selected from the group consisting of O, N-OH, N-OAlq, N-Aryl, N-O-Aryl, N-O-Alk-Aryl.
The compound according to any of the preceding claims, characterized in that R and R 'are each identical or different and are independently chosen from the group consisting of H, Alk.
9. The compound according to any of the preceding claims, characterized in that it is chosen from the group consisting of: 9-hydroxy-3-methoxy-9H-indene [1, 2-b] pyrazine-2-carbonitrile 3-methoxy- 9-Oxo-9H-indene [1,2-b] pyrazine-2-carbonitrile 3-dimethylamino-9-oxo-9H-indene [1,2-b] pyrazine-2-carbonitrile 3- (2-methoxy-ethoxy) ) -9-oxo-9H-indene [1,2-b] pyrazine-2-carbonitrile 3-hydroxy-9-oxo-9H-indene [1,2-b] pyrazine-2-carbonitrile 3-amino-9- oxo-9H-indeno [1,2-b] pyrazine-2-carbonitrile 3- (4,4-difluoro-piperidin-1-yl) -9-oxo-9H-indene [1,2-b] pyrazine-2 -carbonitrile 3-chloro-9-oxo-9H-indene [1,2-b] pyrazine-2-carbonitrile 9- (l 3'-dioxolan-2'-yl) -9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 2-cyano-9- [hydroxyimino] -9H-indene [1,2-b] pyrazine-3-carboxylic acid 9- (methoxyimino) -9H-indene [1, 2-b] ] pyrazine-2,3-dicarbonitrile 9- (allyloxyimino) -9H-indeno [1,2-b] pyrazine-2,3-dicarbonitrile 9-benzyloxyimino-9H-indene [1,2-b] pyrazine-2, 3 -dica rbonitrile 9-Ethoxyimino-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 9-Phenoxyimino-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 6-Methoxy-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 6, 7-dimethoxy-9H-indene [1,2- b] pyrazine-2,3-dicarbonitrile 8-Methyl-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 7,8-dimethoxy-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 6-methyl-9H- indeno [l, 2-b] pyrazine-2,3-dicarbonitrile 5,8-dimethoxy-9H-indene [1,2- b] pyrazine-2,3-dicarbonitrile 6-Methoxy-9-oxo-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 6, 7-dimethoxy-9-oxo-9H-indene [1,2-b] pyrazine-2, 3 -dicarbonitrile 8-Methyl-9-oxo-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 7,8-dimethoxy-9-oxo-9H-indene [1,2-b] pyrazine-2 , 3-dicarbonitrile 6-Methyl-9-oxo-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 5,8-dimethoxy-9-oxo-9H-indene [1,2-b] pyrazine -2, 3-dicarbonitrile 7-Chloro-9-oxo-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 7-Fluoro-9-oxo-9H-indene [1,2-b] pyrazine -2, 3-dicarbonitrile 7-Hydroxy-9-oxo-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile benzo [4,5] thieno [2,3-b] pyrazine-2, 3 -dicarbonitrile 5, 10-dioxo-5, 10-dihydro-benzo [g] quinoxaline-2,3-dicarbonitrile 9- [hydroxyimino] -9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 2- cyano-9-oxo-9H-indeno [1,2-b] pyrazin-3-yl-cyanamide 3- (l-cyano-2-ethoxy-2-hydroxy-vinyl) -9-oxo-9H-indene [1 , 2-b] pyrazine-2-carbonitrile 3-ethylsulfanyl-9-oxo-9H-indene [1,2-b] pyrazine-2-carbonitrile 7-chloro-9-methoxy no-9H-indeno [1,2-b] pyrazine-2,3-dicarbonitrile 9-Allyloxyimino-7-chloro-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 6-chloro-9- oxo-9H-indeno [1,2-b] pyrazine-2,3-dicarbonitrile 2- (2-cyano-9-oxo-9H-indeno [1,2- b] pyrazin-3-yl) -acetamide 9- (2-Phenoxy-ethoxyimino) -9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 7-Chloro-9- (2-phenoxy-ethoxyimino) -9H-indene [l, 2-b] pyrazine-2,3-dicarbonitrile 9-Allyloxyimino-6-chloro-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 7-Fluoro-8-methyl-9-oxo-9H -indeno [l, 2-b] pyrazine-2,3-dicarbonitrile 6, 7-dichloro-9-oxo-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 6-ethyl-9-oxo -9H-indeno [1,2-b] pyrazine-2,3-dicarbonitrile 2-cyano-9- [hydroxyimino] -9H-indene [1,2-b] pyrazine-3-carboxylic acid 9-Allyloxyimino acid -2-cyano-9H-indene [1,2-b] pyrazine-3-carboxylic acid amide 2-cyano-9-ethoxyimino-9H-indene [1,2-b] pyrazine-3-carboxylic acid amide 2-Cyano-9- (2-methoxy-ethoxyimino) -9H-indene [1,2-b] pyrazine-3-carboxylic acid 2-cyano-9-methoxyimino-9H-indene [1, 2-b] amide pyrazine-3-carboxylic acid 2-cyano-9-acetoxyimino-9H-indene [1,2-b] pyrazine-3-carboxylic acid amide of 2-cyano-9-oxo-9H-indene [2] b] pyrazine-3-carboxylic acid ethyl ester (3-carbamoyl-2-cyano-indene [1,2- b] pyrazin-9-ylideneaminooxy) -acetic acid (3-carbamoi) 1-2-cyano-indene [1,2-b] pyrazin-9-ylideneaminooxy) -acetic acid ester of [2- (3-carbamoyl-2-cyano-indene [1,2-b] pyrazine-9] -ylidenoaminooxy) -acetylamino] -acetic acid [2- (3-carbamoyl-2-cyano-indene [1,2-b] pyrazin-9-ylideneaminooxy) -acetylamino] -acetic acid 7-chloro-3-hydroxy-9- oxo-9H-indeno [1,2-b] pyrazine-2-carbonitrile 9 - [(aminocarbonyl) hydrazono] -7-chloro-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile or its saltse , hydrate or pharmaceutically acceptable hydrated salts, or the polymorphic crystalline structures of these compounds or optical isomers, racemates, diastereomers or enantiomers.
The compound according to any of the preceding claims, characterized in that it is selected from the group consisting of: 9-hydroxy-3-methoxy-9H-indene [1,2-b] pyrazine-2-carbonitrile 3-methoxy-9 -oxo-9H-indeno [1,2-b] pyrazine-2-carbonitrile 3-dimethylamino-9-oxo-9H-indene [1,2-b] pyrazine-2-carbonitrile 3- (2-methoxy-ethoxy) -9-oxo-9H-indene [1,2-b] pyrazine-2-carbonitrile 3-hydroxy-9-oxo-9H-indene [1,2-b] pyrazine-2-carbonitrile 3-amino-9-oxo -9H-indeno [1,2-b] pyrazine-2-carbonitrile 3- (4,4-difluoro-piperidin-1-yl) -9-oxo-9H-indene [1,2-b] pyrazine-2 carbonitrile 3-chloro-9-oxo-9H-indene [1,2-b] pyrazine-2-carbonitrile 9- (1 ', 3'-dioxolan-2'-yl) -9H-indene [1, 2-b ] pyrazine-2, 3-dicarbonitrile 2-cyano-9- [hydroxyimino] -9H-indene [1,2-b] pyrazine-3-carboxylic acid 9- (methoxyimino) -9H-indene [1, 2-] b] pyrazine-2,3-dicarbonitrile 9- (allyloxyimino) -9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 9-benzyloxyimino-9H-indene [1,2-b] pyrazine- 2,3-dicarbonitrile 9-Ethoxyimino-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 9-Phenoxyimino-9H-indene [1,2- b] pyrazine-2,3-dicarbonitrile 6-methoxy -9H-indeno [1,2-b] pyrazine-2,3-dicarbonitrile 6, 7-dimethoxy-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 8-Methyl-9H-indene [1 , 2-b] pyrazine-2,3-dicarbonitrile 7,8-dimethoxy-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 6-Methyl-9H-indene [1,2-b] pyrazine -2,3-dicarbonitrile 5,8-dimethoxy-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 6-methoxy-9-oxo-9H-indene [1,2-b] pyrazine-2 , 3-dicarbonitrile 6, 7-dimethoxy-9-oxo-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 8-Methyl-9-oxo-9H-indene [1,2-b] pyrazine -2,3-dicarbonitrile 7,8-dimethoxy-9-oxo-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 6-Methyl-9-oxo-9H-indene [1,2-b] ] pyrazine-2,3-dicarbonitrile 5,8-dimethoxy-9-oxo-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 7-chloro-9-oxo-9H-indene [1, 2 -b] pyrazine-2,3-dicarbonitrile 7-Fluoro-9-oxo-9H-indene [1,2-b] pyrazine-2, 3 -dicarbonitrile 7-Hydroxy-9-oxo-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile benzo [4,5] thieno [2, 3-b] pyrazine-2,3-dicarbonitrile 5, 10-dioxo-5, 10-dihydro-benzo [g] quinoxaline-2,3-dicarbonitrile 2-cyano-9-oxo-9H-indene [1,2-b] pyrazin-3-yl-cyanamide 3- (l -cyano-2-ethoxy-2-hydroxy-vinyl) -9-oxo-9H-indene [1,2-b] pyrazine-2-carbonitrile 3-ethylsulfanyl-9-oxo-9H-indene [1,2-b ] pyrazine-2-carbonitrile 7-Chloro-9-methoxyimino-9H-indene [l, 2-b] pyrazine-2,3-dicarbonitrile 9-Allyloxyimino-7-chloro-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 6-chloro-9-oxo-9H-indene [1 , 2-b] pyrazine-2,3-dicarbonitrile 2- (2-cyano-9-oxo-9H-indeno [1,2- b] pyrazin-3-yl) -acetamide 9- (2-Phenoxy-ethoxyimino) -9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 7-Chloro-9- (2-phenoxy-ethoxyimino) -9H-indene [1,2-b] ] pyrazine-2,3-dicarbonitrile 9-Allyloxyimino-6-chloro-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 7-Fluoro-8-methyl-9-oxo-9H-indene [1 , 2-b] pyrazine-2,3-dicarbonitrile 6,7-dichloro-9-oxo-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 6-ethyl-9-oxo-9H-indene [1,2-b] pyrazine-2, 3-dicarbonitrile 2-cyano-9- [hydroxyimino] -9H-indene [1,2-b] pyrazine-3-carboxylic acid 9-Allyloxyimino-2-cyano acid -9H-indeno [1,2-b] pyrazine-3-carboxylic acid amide 2-Cyano-9-ethoxyimino-9H-indene [1,2-b] pyrazine-3-carboxylic acid 2-Cyano-amide 9- (2-methoxy-ethoxyimino) -9H-indene [1,2-b] pyrazine-3-carboxylic acid 2-cyano-9-methoxyimino-9H-indene [1,2-b] pyrazine-3-amide 2-cyano-9-acetoxyimino-9H-indene [1,2-b] pyrazine-3-carboxylic acid amide of 2-cyano-9-oxo-9H-indene [1,2-b] pyrazine 3-carboxylic ethyl ether of (3-carbamoyl-2-cyano-indene [1,2-b] pyrazin-9-ylideneaminooxy) -acetic acid (3-carbamoyl-2-cyano-indene [1,2-b] pyrazine) 9-ylidenoaminooxy) -acetic acid ester of [2- (3-carbamoyl-2-cyano-indene [1,2-b] pyrazin-9-ylideneaminooxy) -acetylamino] -acetic acid [2- (3-carbamoyl)] -2-cyano-indene [1,2-b] pyrazin-9-ylideneaminooxy) -acetylamino] -acetic acid 7-chloro-3-hydroxy-9-oxo-9H-indene [1,2-b] pyrazine-2- carbonitrile 9- [(aminocarbonyl) hydrazono] -7-chloro-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile or its pharmaceutically acceptable salts, hydrate or ealee hydratae, or the structure of these compounds polymorphic crietalinae or their optical isomers, racemates, diastereomers or enantiomers.
The compound according to any of the preceding claims, characterized in that it is chosen from the group consisting of: 2-cyano-9- [hydroxyimino] -9H-indene [1,2-b] pyrazine-3-amide carboxylic acid 9- (methoxyimino) -9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 9-Benzyloxyimino-9H-indene [1,2- b] pyrazine-2,3-dicarbonitrile (13c). 9-Ethoxyimino-9H-indeno [1,2-b] pyrazine-2,3-dicarbonitrile (13d). 9-Phenoxyimino-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile (13e). 8-Methyl-9-oxo-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 6-Methyl-9-oxo-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 5, 8-dimethoxy-9-oxo-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 7-chloro-9-oxo-9H-indene [1,2-b] pyrazine-2, 3 -dicarbonitrile 7-Fluoro-9-oxo-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 2-cyano-9-o? O-9H-indene [1,2-b] pyrazine Pharmaceutically acceptable 3-carboxylic acid or sueeale, hydrate or hydraeacetate, or polymorphic crystalline structures of these optical compounds or compounds, racemates, diastereomers or enantiomers.
12 The process for the preparation of a conformance set with any of the preceding claims, characterized in that it comprises the step of reacting a corresponding component of the formula (I I) 00 wherein R3, R4, R5, R6, XY, m, m ', n, n' are defined as in formula (I) and R7 'is R7 as defined in formula (I) or a precursor thereof and RV is R1 as defined in formula (I) or a precursor of the mieme.
13. The process according to claim 12, characterized in that Rl 'is CN.
14. The process according to claim 12 or 13, characterized in that - (Y (R7) n.) N- is -C (= 0) -.
15. The processes according to claim 12 to 14, characterized in that the compound of the formula (II) ee obtains a corresponding composition of the formula (III) (lll) (i? r > wherein R3, R4, R5, R6, X, Y, m, m ', n, n' are defined as in formula (I) and R7 'ee is defined as in formula (II).
16. The process according to claim 15, characterized in that when R1 '= CN, this step is carried out in the presence of diaminomaleodinitrile.
17. The procedure according to claim 12 a 14, characterized in that the compound of formula (II) ee obtains a corresponding compound of formula (IV) wherein R 3, R 4, R 5, R 6, X, Y, m, m 1, n, n 'are defined as in formula (I) and R 7"represents R 7' or a precursor thereof, if appropriate.
18. A pharmaceutical composition, characterized in that it comprises a compound of the formula where: (I) m is 0; 1 or 2, wherein when m = 0, (X (R2) m ') m - is none so that it forms an open ring or a single bond; n is 0, 1 or 2,, where when n = 0, - (Y (R7) n ') n - is none so that it forms an open ring or a single bond; m 'and n' are independently 0, 1 or 2; X is a carbon atom or S or N; And it is a carbon atom, or S or N; with the proviso that m and n are not simultaneously 0; ---- are either a single or double link, as appropriate; _____ are either none or a single link, as applicable; Rl is chosen from the group consisting of H, CN, Hal, OAlq, OH, NRCN, C (CN) = C (0H) (OAlq), NRR - (Alq) p-C (O) NRRY Heterocycle, Aryl, Heteroaryl, where Alk, Aryl, Heteroaryl, Heterocycle are optionally substituted by Hal, NRRY CN, OH, CF3, Aryl, Heteroaryl, OAlq and p is 0 or 1; R3, R4, R5, R6 are each identical or different and are independently chosen from the group consisting of H, OAlq, Alk, Hal, NRRY CN, OH, CF3, Aryl, Heteroaryl; R2 is selected from the group consisting of H, O, OH, N-OH, N-Aryl, N-OAlq, N-O-Aryl, NO-Alk-Aryl, N-NR-CONRRY NO-CO-Alk, or R2 linked to the moiety X forms, together with the X, a heterocycle; wherein the Alk, Aryl or heterocycle is optionally substituted by OAlk, Alk, Hal, NRR ', CN, OH, CF3, OAryl, -CO- (NR-Alq-CO) p-OAlq, -CO (NR-Alk -CO) p-OH, where p 'ee 0 or 1; R7 ee chooses from the group that you have of H, O, OH, N-OH, N-Aryl, N-OAlq, N-O-Aryl, NO-Alk-Aryl, N-NR-CONRRY NO-CO-Alk, or 2 R7 linked to the same Y forms together with the Y a heterocycle; wherein the Alkyl, Aryl or heterocycle are optionally substituted by OAlq, Alk, Hal, NRRY CN, OH, CF3, OAryl, -CO- (NR-Alq-CO) p-OAlq, -CO (NR-Alq-CO) p-OH, where p 'is 0 or 1; R and R 'are each identical or different and are independently chosen from the group that H, Alk, where Alk is optionally substituted Hal, NRR', CN, OH, CF3, Aryl, Heteroaryl; or salts, hydrates or pharmaceutically acceptable hydrated salts, or the polymorphic crystalline structures of these optical compounds or dreamomers, racemates, diastereomers or enantiomers.
19. The pharmaceutical composition according to claim 18, characterized in that the compound of the formula (I) is defined as in any of claims 1 to 9.
The pharmaceutical composition according to claim 18 or 19, characterized in that the compound of the formula (I) is chosen from the group you have included: 9-oxo-9H-indeno [1,2-b] pyrazine-2,3-dicarbonitrile 9-hydroxy-3-methoxy-9H-indene [1 , 2-b] pyrazine-2-carbonitrile 3-methoxy-9-oxo-9H-indene [1,2-b] pyrazine-2-carbonitrile 3-dimethylamino-9-oxo-9H-indene [1,2b ] pyrazine-2-carbonitrile 3- (2-methoxy-ethoxy) -9-oxo-9H-indene [1,2-b] pyrazine-2-carbonitrile 3-hydroxy-9-oxo-9H-indene [1, 2 -b] pyrazine-2-carbonitrile 3-amino-9-oxo-9H-indene [1,2-b] pyrazine-2-carbonitrile 3- (4, 4-difluoro-piperidin-1-yl) -9-oxo -9H-indeno [1,2-b] pyrazine-2-carbonitrile 3-chloro-9-oxo-9H-indene [1,2-b] pyrazine-2-carbonitrile 9- (1 ', 3'-dioxolan- 2 '-il) -9H-indeno [1,2-b] pyrazine-2,3-dica 2-cyano-9- [hydroxyimino] -9H-indene [1,2-b] pyrazine-3-carboxylic acid rbonitrile 9- [hydroxyimino] -9H-indeno [1,2-b] pyrazine-2, 3 -dicarbonitrile 9- (methoxyimino) -9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 9- (allyloxyimino) -9H-indene [1,2- b] pyrazine-2,3-dicarbonitrile 9- Benzyloxyimino-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 9-Ethoxyimino-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 9-Phenoxyimino-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 9- [Phenylimino] -9H-indeno [1,2-b] pyrazine-2,3-dicarbonitrile 6-Methoxy-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 6,7-dimethoxy- 9H-indeno [l, 2-b] pyrazine-2,3-dicarbonitrile 8-Methyl-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 7,8-dimethoxy-9H-indene [1,2- b] pyrazine-2,3-dicarbonitrile 6-Methyl-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 5,8-dimethoxy-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 6-methoxy-9- oxo-9H-indeno [1,2-b] pyrazine-2,3-dicarbonitrile 6, 7-dimethoxy-9-oxo-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 8-methyl- 9-Oxo-9H-indeno [1,2-b] pyrazine-2,3-dicarbonitrile 7,8-dimethoxy-9-oxo-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 6- Methyl-9-oxo-9H-indeno [1,2-b] pyrazine-2,3-dicarbonitrile 5, 8-Dimethoxy-9-oxo-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 7-chloro-9-oxo-9H-indene [1,2-b] pyrazine-2, 3 -dicarbonitrile 7-Fluoro-9-oxo-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 7-Methoxy-9-oxo-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 7-Hydroxy-9-oxo-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile benzo [4,5] thieno [2,3-b] pyrazine-2,3-dicarbonitrile 5, 10- dioxo-5, 10-dihydro-benzo [g] quinoxaline-2,3-dicarbonitrile 2-cyano-9-oxo-9H-indeno [1,2-b] pyrazin-3-yl-cyanamide 3- (l-cyano) -2-ethoxy-2-hydroxy-vinyl) -9-oxo-9H-indene [1,2-b] pyrazine-2-carbonitrile 3-ethylsulfanyl-9-oxo-9H-indene [1,2-b] pyrazine -2-carbonitrile 7-Chloro-9-methoxyimino-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 9-Allyloxyimino-7-chloro-9H-indene [1,2-b] pyrazine-2 , 3-dicarbonitrile 6-Chloro-9-oxo-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 2- (2-cyano-9-oxo-9H-indene [1,2-b] pyrazin-3-yl) -acetamide 9- (2-phenoxy-ethoxyimino) -9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 7-chloro-9- (2-phenoxy-ethoxyimino) -9H -indeno [1,2-b] pyrazine-2,3-dicarbonitrile 9-Allyloxyimino-6-chloro-9H-indene [1,2-b] pyrazine-2 , 3-dicarbonitrile 7-Fluoro-8-methyl-9-oxo-9H-indeno [1,2-b] pyrazine-2,3-dicarbonitrile 6, 7-dichloro-9-oxo-9H-indene [1,2] -b] pyrazine-2,3-dicarbonitrile 6-ethyl-9-oxo-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile 2-cyano-9- [hydroxyimino] -9H- amide indene [l, 2-b] pyrazine-3-carboxylic acid 9-Allyloxyimino-2-cyano-9H-indene [1,2-b] pyrazine-3-carboxylic acid amide 2-cyano-9-ethoxyimino-9H amide -indeno [1,2-b] pyrazine-3-carboxylic acid 2-cyano-9- (2-methoxy-ethoxyimino) -9H-indene [1,2-b] pyrazine-3-carboxylic acid amide -Ciano-9-methoxyimino-9H-indeno [1,2-b] pyrazine-3-carboxylic acid 2-cyano-9-acetoxyimino-9H-indene [1,2-b] pyrazine-3-carboxylic acid amide 2-cyano-9-oxo-9H-indene [1,2-b] pyrazine-3-carboxylic acid ester of (3-carbamoyl-2-cyano-indene [1,2-b] pyrazine-9-) ilidenoaminooxy) -acetic acid (3-carbamoyl-2-cyano-indene [1,2-b] pyrazin-9-ylideneaminooxy) -acetic acid ester of l [2- (3-carbamoyl-2-cyano-indene [1,2-b] pyrazin-9-ylideneaminooxy) -acetylamino] -acetic acid [2- (3-carbamoyl-2-cyano-indene [1]] 2-b] pyrazin-9-ylideneaminooxy) -acetylamino] -acetic acid 7-chloro-3-hydroxy-9-oxo-9H-indene [1,2-b] pyrazine-2-carbonitrile 9- [(aminocarbonyl) hydrazone] -7-chloro-9H-indene [1,2-b] pyrazine-2,3-dicarbonitrile or salts, hydrates or pharmaceutically acceptable hydrated salts, or the polymorphic structures of these compounds or their optical isomers, racemates, diastereomers or enantiomers
21. The use of a compound of the formula (I) as defined in accordance with any of claims 18 to 20 for the preparation of a medicament for inhibiting one or more cysteinae proteaeae.
22. The use according to claim 21, wherein the cysteine proteases are one or more groups of deubiquitination enzymes, caspaeae, cathepeins, calpains as well as parasitic, viral, bacterial, or fungal cysteines protease.
23. The use of a compound of the formula (I) as defined according to any of claims 18 to 20, for the preparation of a medicament for treating and / or preventing cancer and metastasis, neurodegenerative diseases, such as Alzheimer's disease and Parkineon disease, inflammatory traumas, cardiovascular diseases and / or viral infectivity and / or latency in particular for Herpes simplex virus-1, Epstein-Barr virus or Corona virus SARS.
24. The use according to claim 23, wherein the compound inhibits one or more deubiquitination enzymes.
25. The use of a compound of the formula (I) as defined according to any of claims 18 to 20, for the preparation of a medicament for treating and / or preventing inflammatory disorders, neurodegenerative disorder, preferably nerve cell damage. caused by stroke, liver damage and liver failure as a result of acute or chronic infections, ischemic or chemical liver disease, kidney damage and renal failure resulting from acute or chronic infections, kidney injury or chemistry, heart failure and cardiac inefficiency resulting from infections acute or chronic, chemical or ischemic cardiac injury, diabetes resulting from oxidative or metabolic lesions, chemical, acute or chronic autoimmune to insulin beta cells of pancreatic islets.
26. The process according to claim 25, wherein the compound inhibits one or more caspaeae.
27. The use of a compound of the formula (I) as defined in accordance with any of the claims 18 to 20 for the preparation of a medicament for treating and / or preventing cancer and metastasis, cardiovascular diseases, immune disorders, bone and joint diseases, osteoporosis and arthritis.
28. The procedure according to claim 27, wherein the compound inhibits one or more cathepsinae.
29. The use of a compound of the formula (I) as defined according to any of claims 18 to 20 for the preparation of a medicament for treating and / or preventing aging disorders, late onset diabetes and cataracts.
30. The process according to claim 29, wherein the compound inhibits one or more calpains.
31. The use of a compound of the formula (I) as defined in accordance with any of the claims 18 to 20 for the preparation of a medicament for treating and / or preventing infectious and viral diseases.
32. The use according to claim 31, wherein the infectious and viral diseases are selected from hepatitis A, hepatitis C, Coronavirus SARS infection and disease, rhinoviral infections and diseases, adenoviral infection and disease, poliomyelitis.
33. The use according to claim 31 or 32, wherein the compound inhibits one or more viralee protease cysteines.
34. The use of a compound of the formula (I) as defined in accordance with any of claims 18 to 20 for the preparation of a medicament for treating and / or preventing bacterial infections and diseases.
35. The use according to claim 34, wherein the bacterial infections or diseases, choose from streptococcal infections and diseases, infections and diseases trapped by the bacterium of the species of the genus Cloetridium, infections and diseases of staphylococci, gingivitis and Periodontal diseases.
36. The use according to claim 34 or 35, wherein the compound inhibits one or more bacterial cysteine proteases.
37. The use according to any of claims 34 to 36, wherein the composition inhibits one or more bacterial cysteines proteases chosen from etreptopatin, cloetripain, staphylococcal cysteine protease, gingipain.
38. The use of a compound of the formula (I) according to any of claims 18 to 20 for the preparation of a medicament for treating and / or preventing infections and fungal diseases.
39. The use according to claim 38, wherein the compound inhibits one or more fungal cysteines proteases.
40. The use of the compound of the formula (I) as defined in any of claims 18 to 20 for the preparation of a medicament for the treatment and / or prevention of infection and disease of paraeitoe protozoarioe.
41. The process according to claim 40, wherein the compound inhibits one or more cysteine proteases of protozoan parasites.
42. The use of the compound of the formula (I) as defined in any of claims 18 to 20 for the preparation of a medicament for treating and / or preventing infections and diseases of flat geuee paraeitoe.
43. The use according to claim 42, wherein the compound inhibits one or more cysteine proteases of flatworm paraeitoe.
44. The use of a compound of the formula (I) as defined in any of claims 18 to 20 for the preparation of a medicament for treating and / or preventing infections and diseases by round worm parasites.
45. The use according to claim 44, wherein the compound inhibits one or more cysteine proteaeae from round geue paraeitoe.
46. The procedure according to any of claims 23 to 45, wherein the medicament is used in combination with one or more therapies chosen from anti-cancer therapies, neurological therapies, thrombolytic therapies, antioxidant therapy, anti-infection therapies, antihypertension, therapies. diuretics, thrombolytic therapies, immunosuppressive therapies, cardiovascular therapies, immunomodulatory therapies, anti-inflammatory therapies, anti-viral therapy, antibacterial therapies, anti-fungal therapy, anti-protozoal therapy, anti-parasitic therapies.